Enaminone

The acid promoted cyclization of AT-(2-chloroallyl)enaminones (Scheme 35a) provides the expected 3-methyltetrahydroindoles, whereas similar treatment of iV-(2-chloroallyl)anilines yields unexpectedly 2-, rather than 3-, methylindoles (Scheme 35b) (75JCS(Pl)U46). The course of the latter cyclization is not resolved although various intermediates, such as those shown, have been considered. The ring closure in the furan synthesis shown in Scheme 35c is catalyzed by mercury(II) ion (79JCs(Pl)316l). 

Isoxazoles are readily cleaved under reducing conditions, and many examples have been reported (79AHC(25)147,63AHC(2)365). In the last three decades the potential of these reactions in synthesis has finally been realized, and the isoxazole ring has become a major tool as a masked enaminone (137) or 1,3-diketone, particularly for the synthesis of heterocycles. 

Applications of the isoxazole ring as a masked enaminone for the synthesis of various heterocycles are shown in Scheme 38. 

Reaction of benzonitrile A-oxide with benzoylacetylene gave a mixture of 4-benzoyl-isoxazole (347) and 5-benzoylisoxazole (348), whereas that with )3-enaminone (349) gave exclusively 4-benzoylisoxazole (347) (71S433) and that with chloroenone (350) gave exclusively 5-benzoylisoxazole (348) (70S344). 

The thiation procedure described here is an example of a general synthetic method for the conversion of carbonyl to thiocarbonyl groups. Similar transformations have been carried out with ketones, carboxamides,esters,thioesters, 1 actones, " thiol actones, - imides, enaminones, and protected peptides. ... 

Enaminones as versatile intermediates for alkaloid synthesis 99PAC979. 

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. 

In a similar process, tertiary enaminones react with alkynylcarbene complexes to give the corresponding pyranylidene complexes following a reaction pathway analogous to that described above. First, a [2+2] cycloaddition reaction between the alkynyl moiety of the carbene complex and the C=C double bond of the enamine generates a cyclobutene intermediate, which evolves by a conrotatory cyclobutene ring opening followed by a cyclisation process [94] (Scheme 49). 

Mit Trifluoressigsaure protonierte Enaminone werden mit Natriumboranat in Isopropanol zu den entsprechenden a, /3-ungesattigten Ketonen reduziert9 und/3-Dialkylami-no-enone ergeben mit Natriumboranat/Eisen(III)-chlorid gesattigte Amino-alkohole10. Zur Reduktion von Aryl-, Methoxy- usw. Enamino-ketonen s.Lit.11. 

Scheme 2 Examples of synthesis of 2-pyridones either from 1,3-diketones (a b) or from enaminones (c d)...

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

Fig. 2 A library of 18 different functionalized 2-pyridones 8 were synthesized from enaminones 7 using microwave irradiation (single mode) [42]...

Fig. 3 Tentative mechanism for the formation of substituted 2-pyridones in the reaction between enaminones and methylene-activated nitriles...

Conventional conversion of amide, lactam, imide, and urea carbonyl groups into enaminones, enamino esters, or enamino nitriles requires prior activation of the carbonyl groups either by alkylation to imino ethers, followed by reaction with activated methylene groups, or by thiation, e.g. with P2S5, to thiocarbonyl groups followed by alkylation (and possibly also oxidation), and, again, subsequent reac-... 

If the enaminone contains one N-methyl group as in 733 a, a mixture of the pyridine 732 and the substituted benzene 735 is obtained, whereas with two N-al-... 

In this context, also mentionable are several publications by the groups of Dlaz-de-Villegas [242], Guarna [243], Kunz [244] and Waldmann [245], which describe the formation of six-membered azaheterocycles via treatment of an imine with an appropriate substituted diene. For instance, as described by Waldmann and coworkers, reaction of the enantiopure amino acid-derived imines 2-452 with Danishefsky s diene 2-453 in the presence of equimolar amounts of a Lewis acid provided diastereomeric enaminones 2-456 and 2-457 (Scheme 2.105) [245a]. 

Again, using a Pd-catalyzed amidation as the first step, Edmondson and coworkers [162] developed a synthesis of 2,3-disubstituted indoles 6/1-340 by reaction of 6/1-337 and 6/1-338 with catalytic amounts of Pd2(dba)3 and the ligand 6/1-341. On order to achieve good results, a second charge of Pd had to be added after 12 h. In the first step the enaminone 6/1-339 is formed, which then cydizes in a Heck-... 

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>. 

A short review has been published on the utilization of chiral enaminones and azomethine imines in the synthesis of functionalized pyrazoles <06ARK35>. 

SL901>. Reductive cleavage of 5-silyl, 3-, 4- and 5-silylmethylisoxazoles gave their corresponding silyl P-enaminones, which on reaction with hydrazines, provided regioselective syntheses of 3- or 5-silylpyrazoles and 3-, 4- or 5-silylmethylpyrazoles, respectively <06T611>. 

Reductive cleavage of 5-silyl-, 3-, 4-, and 5-silylmethylisoxazoles 1 gave silyl (3-enaminones 2, useful synthons in the regioselective synthesis of silyl- and silylmethylpyrazoles 3, as well as pyrrole-, pyrimidine-, and pyridine derivatives <06T611>. 

In an alternate use of a palladium-catalyzed C-N bond forming reaction, Edmondson described the first example of the coupling of vinylogous amides (e.g., 96) to aryl halides. In addition to the formation of W-aryl enaminones 97, this reaction could be applied in a tandem... 

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