Ketoesters and Ketoamides

Some neutral rhodium catalysts with chiral ligands, such as MCCPM 9 (see Scheme 33.3) [20c], Cy,Cy-oxoProNOP 15, and Cp,Cp-IndoNOP 18, demonstrate excellent enantioselectivities and reactivities in the hydrogenation of a-ketoesters and ketoamides indeed, they compare well with ruthenium-based catalysts (Table 33.2). Togni et al. have successfully used the Josiphos 47 ligand for the hydrogenation of ethyl acetoacetate [27], while the use of MannOPs has led to somewhat high enantioselectivities [18]. 

Moreno-Manas et al. [98] reported on a similar effect of triphenylphosphine for the Michael addition of active methylene compounds to n-acceptor olefins such as methyl vinyl ketone, acrylonitrile, and 2-vinylpyridine and dialkyl azodi-carboxylates. They compared the reactivity of RuH2(PPh3)4, RuCl2(PPh3)3, and PPh3 and concluded that for /5-diketones, ketoesters, and ketoamides, triphenylphosphine released from the ruthenium complexes contributes totally or partially to the catalysis. 

Finally, Ma et al. further elaborated on this chemistry toward the development of an efficient cascade process for the assembly of 2,3-disubstituted indoles 296 (Scheme 9.102) [239,272]. The authors showed that an array ofaliphatic and aromatic P-ketoesters and ketoamides 295 could be utilized in the 3 +2 annulation reaction with anilides 294 providing the corresponding indoles 296 in moderate to excellent yields. In addition, this reaction was applied to 2-bromotrifluoroacetanilides, albeit requiring slightly elevated temperatures to achieve complete conversion. It is believed that cydocondensation of aminoketone 298 accomplished the indole ring... 

To date, few examples of organocatalytic asymmetric addition of nitromethane to ketones have been reported and all of them involve activated ketones, mainly ketoesters and ketoamides. 

The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three elasses of putative transition-state inhibitors a-trifluoromethyl ketones, a-ketoesters and a-ketoamides [62], In the initial sereening studies, it was found that the trifluoromethyl ketone eompounds tested were effeetive inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Roger and co-workers [63]. 

As part of our efforts to develop new efficient one-pot methodologies to access novel heterocyclic structures, we also reported an efficient synthesis of spiro[4,61-lactones and lactames by sequential multicomponent reaction/metal-catalyzed carbo-cyclizations from simple five-membered cyclic (3-ketoesters and (3-ketoamides,... 

The dicationic species have also been obtained from /3-ketoacids, fi-ketoesters, and /-i-ketoamides in superacid solutions (Table 1, entries 2-4). Diprotonated acetoacetic acid (75) can be observed by low-temperature NMR under stable ion conditions.34 Likewise, diprotonated methylacetoacetate (77) can be observed by NMR at temperatures lower than — 80°C in FS03H-SbF5-SC>2 solution.35 With ethyl acetoac-etate in HF-SbFs, the equilibrium constant for the dication-monocation equilibrium has been estimated to be at least 107, indicating virtually complete conversion to the superelectrophile.35 The /3-ketoamide (78) is found to give the condensation products 95 in good yield from CF3SO3H and the superelectrophile 79 is proposed as the key intermediate in the condensation reaction (eq 25 ).27... 

With )3-ketoesters, /3-ketoamides and )3-diketones, DAMN is converted into enamines, which can be cyclized purely by heating in an alcoholic solvent. The products are 2-substituted-4,5-dicyanoimidazoles (Scheme 2.1.5) [45], When DAMN reacts with formamidine, the initial condensation product (16)/(17) can form imidazoles either by loss of ammonia (when 4,5-dicyanoinnidazole is formed), or via an isomerization and subsequent cyclization which eliminates HCN to give 4-ainino-5-cyanoimidazole (18). With excess formamidine the latter product is converted into adenine. The intermediate amidines (16)/(17), as transient intermediates, react with aqueous ammonia to form (18), and with acetic acid to give (15) (R = R = H) [48, 50]. The transformation of (17) to (18) is a 1,5 bond formation (Scheme 2.1.6). 

Microwave-assisted syntheses of pyrazoles and isoxazoles have been achieved by cyclocondensation reactions of R-ketoesters and P-ketoamides, l-(dimethoxyme-thyl)imidazole, and hydrazines or hydroxylamine on a solid phase, using a novel aminophenyl-substituted cellulose resin [86]. 

TBAF-assisted Trifluoromethylation, Perfluoroalkylation, and Polyfluoroalkoxylation. TBAF combines with TMSCF3 to form nucleophilic trifluoromethyl anion equivalents. The precise structure of this nucleophile is unknown, although it is likely that a pentacoordinate silicon intermediate is involved. The TBAF/TMSCF3 combination leads to smooth trifluoromethylation of aldehydes,ketones, esters, imines, nitroso compounds, a-ketoesters, Q -ketoamides (eq and... 

METHOD a with CATALYST AND SOLVENT To a 50-mL, two-ncckcd, round-bottom flask flushed with Ar and equipped with a magnetic stirring bar and a reflux condenser were added 1,2-dichloroethane freshly distilled over CaCl2 (25 mL), commercially available nonactivated 4 A MS (6 g), p-ketoester, p-ketoamide 79 (or p-ketosulfone not shown) (1.28 mmol), aldehyde 78 (1.5 mmol), and diamine 77 (1.28 mmol). The heterogeneous mixture was stirred at reflux under Ar for 24 h. The solution was filtered through a short pad of Celite, which had been thoroughly washed with DCE. The solvent was evaporated under reduced pressure to afford the crude compound, which was purified by flash chromatography over silica gel. 

Catalyst for Conjugate Additions. The catalytic effect of copper(II) chloride on the 1,4-addition of /3-dicarbonyl compounds to (arylazo)alkenes and aminocarbonylazoalkenes has been studied in some detail. The reactions proceed at ambient temperature in THF and afford the corresponding pyrrole derivatives (eq 15). This mild method requires no other catalyst and succeeds with 8-diketones, /3-ketoesters, and /3-ketoamides. Copper(II) chloride also catalyzes the addition of water, alcohols, phenol, and aromatic amines to arylazoaUcenes (eq 16). ... 

In a similar manner, using the same catalytic system and conditions [FeCla (20 mol%), BuOO Bu (2 equiv.), 80 °C, 8-36 h], diatylmethane derivatives can react efficiently with p-ketoesters, p-ketoamides and p-diketones (Scheme 4.3). ... 

The Hantzsch reaction that allows the synthesis of pyridine derivatives, is a condensation involving two equivalents of a yS-ketoester or a yS-ketoamide, one equivalent of an aldehyde and ammonia. The Hantzsch reaction was used by Patel et al. for the synthesis of a 300 member dihydropyridine library (Scheme 3.27) [287]. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

Recently, it has been shown that /1-diketones [126],/ -ketoesters (Fig. 48) [126] and N, N-dialkyl-/ -ketoamides [127] can be fluorinated directly, in high yield, at convenient temperatures (0 10 °C), in polar solvents such as formic acid or acetonitrile. As in the case of the pyruvates, the overall rate of reaction was a... 

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)]. ... 

Oxime 5 was synthesized by treatment of t-butyl acetoacetate with sodium nitrite in acetic acid. Reaction of 5 wim p-ketoamide 6 in me presence of zinc and acetic acid according to the classic Knorr pyrrole formation conditions led to pyrrole 12. Aimough mis reaction worked fairly well (60 to 70% yield), workup and product isolation proved problematic as the reaction scale was increased (>10 g). Typically, the products of Knorr reactions (when p-ketoesters are used instead of p-ketoamides) are isolated by a water knock-out at me end of me reaction. However, in the case of 12, me presence of me pendant amine functionality rendered precipitation of the product from an acidic reaction mixture impossible. Precipitation of me product required basic conditions unfortunately, at pH 9, gelatinous zinc salts crashed out of solution, making an extraction or isolation... 

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