Of enaminones

A 3,4,8,9-tetrahydropyrido[2,l-c][l,4]thiazine 336 and a benzo(A)-l,4-thiazine 335 was isolated from the reaction mixture of enaminone 334 and 2-(3-chlorobenzylidene)acetylacetate (99T7915). Reactions of enamines 334 and 337 with DMAD in MeOH yielded addition products 338 and 339 and bi- and tricyclic derivatives 340 and 341, respectively. The latters could be obtained in quantitative yields when the addition products 338 and 339 were heated in refluxing MeOH. 

The reaction of enaminones with nitroalkenes gives a pentalenone system via the Michael addition and aldol reaction (Eq. 4.66).85a Linear a-keto enamines react with nitroalkenes to afford [3 + 2] carbocyclized products.8515... 

A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel-Crafts heteroannulation of enaminone precursors <06SL749>. A lac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <06OL3573>. 

When the reaction of enaminone (223) and dimethyl methoxymethy-lenemalonate was carried out in THF in the presence of butyllithium, pyrrolidinomethylenemalonate (224) was obtained in 4% yield. When this reaction conducted in DMF in the presence of potassium tert-butylate, pyrrolidinomethylenemalonate (224) and 2,3-dihydro- l//-indolizin-5-one (225) were prepared in 21 and 46% yields, respectively (88AP345). 

Fig. 11.8. Formation and tautomeric equilibria of enaminones (11.63) as potential prodrugs...

V. H. Naringrekar, V. J. Stella, Mechanism of Hydrolysis and Structure-Stability Relationship of Enaminones as Potential Prodrugs of Model Primary Amines , J. Pharm. Sci. 1990, 79, 138 - 146. 

The electrode processes on the voltammetric and the preparative electrolysis time scales may be quite different. The oxidation of enaminone 1 with the hydroxy group in the ortho position under the controlled potential electrolysis gave bichromone 2 in 68% yield (Scheme 4.) with the consumption of 2.4 F/mol [21], The RDE voltammogram of the solution of 1 in CH3CN-O.I mol/1 Et4C104 showed one wave whose current function, ii/co C, was constant with rotation rates in the range from 1(X) to 2700 rpm and showed one-electron behavior by comparison to the values of the current function with that obtained for ferrocene. The LSV analysis was undertaken in order to explain the mechanism of the reaction which involves several steps (e-c-dimerization-p-deamina-tion). The variation of Ep/2 with log v was 30.1 1.8 mV and variation of Ep/2 with logC was zero. Thus, our kinetic data obtained from LSV compare favorably with the theoretical value, 29.6 mV at 298 K, for a first order rate low [15]. This observation ruled out the dimerization of radical cation, for... 

Oxidation of enaminone 1 is initiated by electron loss from the dimethylamino moiety leading to radical cation, RH". The following chemical reaction would be an intramolecular cyclization through addition of a hydroxy group on the radical cation site yielding a cyclic radical cation, cRH ". This step is most likely the rate-determining step. The cyclic radical cation then dimerizes... 

In the recent study on the anodic oxidation of enaminones which possess an unsaturated chain susceptible to react intramolecularly with an electrogenerated radical cation, the evidence for an intramolecular reaction was provided on the basis of the dEp/dlogv slope of 30 mV and one-electron behavior of the voltametric wave [48], The reaction could involve similar mechanistic pathways as shown in Scheme 4 (e-c-dimerization and following chemical reactions). However, the authors were not able to isolate the products after preparative oxidation in order to confirm the possible mechanism. 

The radical cations generated at the anode surface can dimerize before they diffuse into solution. The dimeric compound formed can then be cyclized in solution via formation of a carbon-heteroatom bond. The anodic oxidation of enaminones reported earlier [46] and also recently [47] could serve as an illustration of this type of intermolecular cyclization. 

Anodic oxidation of enaminone 10 was performed at the platinum gauze electrode in methanol solution containing LiC104 in a divided cell at controlled potential. After passage of 1.2F/mol two major products 11 and 12 were isolated in 50 and 20% yields respectively (Scheme 12). Oxidation of the enaminone 10 is initiated by electron loss from the dimethylamino moiety to... 

The mechanism for the transformation of enaminones 1 via anodic oxidation to bischromones 72 was discussed in Sect. 2.1. Since the enaminones can be easily prepared from available o-hydroxyacetylarenes the reaction shown in Scheme 36 represents a general method for the synthesis of the corresponding bischromones which can be obtained in good yields [21]. 

Another example of a MCR-based strategy for the synthesis of pyridines was reported by Kantevari et al. in 2007. Thus, the three-component condensation of enaminones, 1,3-dicarbonyls, and ammonium acetate in the presence of a catalytic amount of a tangstocobaltate salt as heterogeneous catalyst, either in refluxing solvent or under solvent-free conditions, allowed the regioselective formation of 2,3,6-trisubstituted pyridines and 2,7,7-trisubstituted tetrahydroquinolin-5-ones (Scheme 55) [155]. This methodology combines shorter reaction times and... 

The N-acylation product of the reaction of enaminones with either 2-chloronicotinoyl chloride or 2,6-dichloro-5-fluoronicotinoyl chloride readily undergoes cyclization (either directly or on treatment with sodium hydride) to give high yields of 8-acyl-7-alkyl[l,6]naphthyridin-5(6//)-ones, which themselves are attractive precursors for elaboration to naphtho[2,3-, ][l,6]naphthyridin-5-ones and pyrido[2,3-f][l,6]naphthyridin-6-ones <2002T58>. 

The majority of reactions required to form these types of heterocycles involve the condensation of a 1,2-diamine and a 1,2-dicarbonyl compound, as shown in Equation (46) <2000H(52)423>. Other examples include the reaction of enaminones with carboxamides (Equations 47 and 48) <199681012, 2000T8489> and the cyclocondensation of a-ketoesters (Equation 49) <2001FA933>. Nicolaou and Li have prepared 99 and 100 by reaction of the diol 101 with a-bromoisobutyraldehyde (Equation 50) <2001AGE4264>. 

Antibody Catalysis. Recent advances in biocatalysis have led to the generation of catalytic antibodies exhibiting aldolase activity by Lemer and Barbas. The antibody-catalyzed aldol addition reactions display remarkable enantioselectivity and substrate scope [18]. The requisite antibodies were produced through the process of reactive immunization wherein antibodies were raised against a [Tdiketone hapten. During the selection process, the presence of a suitably oriented lysine leads to the condensation of the -amine with the hapten. The formation of enaminone at the active site results in a molecular imprint that leads to the production of antibodies that function as aldol catalysts via a lysine-dependent class I aldolase mechanism (Eq. 8B2.12). 

Cadmium salts and organocadmium reagents also have found applications in cyclization reaction. Cadmium-mediated cyclization of enaminone occurs under mild conditions, whether in presence of a base and a cadmium(ll) salt (60 to 90 °C), or in the presence of dibutylcadmium at room temperature (Equation (181)). 

A simple formula has been proposed71 to calculate <5H(2) of enaminones 322 (R2 = H) in any of their four isomeric forms A-D (Scheme 5) ... 

Although the reactivity of enaminones is not always the same as that of typical enamines due to the additional conjugative interaction with the carbonyl group, the anodic oxidation of enaminones seems useful in organic synthesis since they yield dimerized or cyclized products upon anodic oxidation. In anodic oxidation of the enaminones or enaminoesters in methanol containing sodium perchlorate, for instance, derivatives of pyrrole are formed via initial dimerization (equation 4)5. 

The term enaminone is used to indicate any compound containing the conjugated system N—C=C—c=0582,583. It may be a mono-enamine of 1,3-diketone or of a 3-keto ester. A general method for the preparation of enaminones involves reaction between ammonia or primary or secondary amine and a 1,3-diketone (3-chloro(bromo)-2-alkenone) or a 3-ketoester584"590. An improved procedure employed ammonium and amine acetates591 (equation 38). 

The addition of a base to an acetylenic ester or ketone provides another method of preparation of enaminones594,595. A convenient one-pot synthesis of enaminones from trimethylsilylethynyl ketones and amines was described596. The reaction of activated methylene compounds, such as cycloalkanones, MeCOPh and PhCH2COOMe, with amide acetals gave high yields of enaminones597 (equation 39). 

Mannich reaction of CH(OEt)3, a ketone MeCOR [R = Et, Me2CHCH2, Ph, o-C6H4(CH2)2, p-ClC6H4, p-anisyl, 2-thienyl, 2-pyridyl, 2-furyl] and RjNH (R1 = Me, Et NRj = piperidino, morpholino) gave 33-80% of enaminones RCOCH=CHNR2 5". 

Though the chemistry of enaminones is well established, it has not yet been reviewed except for Greenhill s 1979 article.16... 

Enaminones are useful and widely used synthons in organic synthesis of alicyclic, aromatic and heterocyclic compounds. Frequently, it is assumed that enaminones are formed as intermediates in the synthesis of heterocycles. However, when they are not isolated, they are not considered in this article. Moreover, there are many examples of formal analogues of enaminones (e.g. aromatic or quinonoid compounds) as well as heterosubstituted derivatives4 which are also not discussed in the present chapter. 

By suitable substitution the enaminones can often serve as precursors for heterocycles and preparation of indoles, carbazoles, quinolines, acridines and phenaNthridines can be achieved easily. However, this part of enaminone chemistry can lead to surprising and unexpected reactions if the multifunctional properties of the enaminones are ignored, e.g. ring contraction, ring expansion and other rearrangements are observed. In some cases jft-ketoenamines react as the ene-component in cycloaddition. Enaminones are even suitable synthones for building aromatic rings. 

Reaction of tertiary enaminones with benzoyl isothiocyanate gives substituted 2-pyridinethiones in moderate yields, indicating the reactivity of enaminones at a-methyl group6 (equation 2). Phenylisothiocyanate reacts simply at the -position7 (equation 3). 

An interesting substitution by sulphur at the -position is performed in a special type of enaminone with thiocyanate anion (equation 5). 

The ambident nucleophilic character of enaminones is again demonstrated by the reaction with keto carbenes, produced in situ from diazoketones. Acyclic enaminones react via the -position to directly yield pyrroles (equation 11). Cyclic enaminones are shown to react at the nitrogen to give adducts which can be cyclized with KOH to... 

Condensation of primary dimedone enaminones with formaldehyde according to Greenhill and coworkers26,27 give, in neutral medium, methylenbisenaminones, whereas acidic conditions produce spirocompounds. Structure A is given by Greenhill27 for the spiro-product, but structure B (equation 20) also seems reasonable. Modern spectroscopic methods should be used to solve this problem. Similar products are obtained in the Mannich reaction of enaminones derived from indan-l,3-dione33. 

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