A Ketoenamines

Chiral a-ketoenamines.1 The a-ketoenamine 2 is obtained by reaction of 1,2-cyclohexanedione with 1 in benzene in the presence of molecular sieves. Grignard reagents add to 2 to provide (R)-3 in high optical purity. Surprisingly, alkyllithiums add to 2 to give (S)-3, but usually in lower optical yields. 

In order to define the scope, it seems useful to distinguish between / -ketoenamines (the term for enaminones resulting from 1,3-dicarbonyls, according to Greenhill) and a-ketoenamines (the term for the enamines derived from 1,2-dicarbonyls). 

Reaction of cyclic / -ketoenamines with diethyl diazene dicarboxylate is observed to yield Michael-type adducts85,86 (equation 61). For aromatization of the products see Section II.A.5. In contrast, the corresponding a-ketoenamine reaction leads to heterocyclic Diels-Alder adducts (see Section IV). 

Other extensions of the Nenitzescu reaction are the use of a-ketoenamines (see equations 233-235) which mainly yield non-indolic compounds. Another extension is the application to -substituted aminomethylene ketones leading to compounds with indole-2-one structure by rearrangement (see Section II.B, equations 158-160). 

Little is known so far about a-ketoenamines, probably because they are sometimes not directly accessible from the corresponding diketones. Nevertheless, they are useful synthones, especially for heterocyclic synthesis. Compared with / -ketoenamines, the chemical behaviour of the a-keto-derivatives is somewhat different. They react as enamines, as well as a,/ -unsaturated ketones, which means that they act either as an electrophile or as a nucleophile in the -position. For example, protonation usually occurs at the fi-C atom with subsequent enolization308. Aminomethylation according to Mannich takes place in the -position as well309. The alkylation with alkyl halide, however, is reported to occur at nitrogen310,311. In addition to electrophilic and nucleophilic chemistry, a-ketoenamines are useful synthons in photochemistry and electrocyclic reactions. 

In a typical enamine reaction, a-ketoenamines with suitable N-substitution are converted to indol-7-ones although in low yield312 (equation 230). Better methods starting from a-ketoenamines are known (equations 231 and 242). 

A homoveratryl enaminone derived from cyclohexane-1,2-dione was cyclized through a 1,4-addition at the a,/ -unsaturated ketone moiety of the enaminone319 (equation 237). The spiro compound obtained, which is a useful intermediate in the synthesis of erythrina-alkaloids, demonstrates the special character of a-ketoenamines. 

The surprising rearrangement of an aminocycloheptenone to the aminoacylcyclo-pentenone skeleton321 is achieved by a nucleophilic attack of the hydroxide ion at the -position of an enaminone, a special reaction known only for a-ketoenamines. This step is followed by a retro-aldol cleavage of the cycloheptanone ring and a subsequent aldol cyclization yields the cyclopentane derivative (equation 240). 

Whereas cyclic secondary enaminones and nitroolefins mainly yield indoles in which the enamine nitrogen is incorporated into the heterocyclus (equation 242), linear tertiary a-ketoenamines are shown to react with nitroolefines at low temperature under kinetic control to give 1,2-oxazine N-oxides as [4 + 2]-cycloadducts, followed by retro-Diels-Alder reaction or rearrangement under thermodynamic control which leads diastereo-selectively to aminocyclopentenes. The reaction is called [3 + 2]-carbocyclization, apparently because the ketoenamine is reacting as a 1,3-dipole. The products are hydrolysable to polysubstituted nitrocyclopentanones with retained configuration325 (equation 243). 

In [3 + 2]-cycloaddition reactions a-ketoenamines serve as synthons, reacting with phenyl azide as the 1,3-dipole component. The resulting tetrahydrophenylcyclopenta-triazol-4-ones are interesting and easily accessible heterocycles329 (equation 247). 

Indolines, including spiro compounds, are synthesized in good yield by photoarylation of compounds having the JV-aryl a-ketoenamine structure331 (equations 249 and 250). 

The photochemical behavior of aminocyclohexenones depends on the substituents on nitrogen. Cyclization of iV-arylketoenamines to 2-carbazolones is achieved photochemic-ally332 (equation 251). However JV-benzyl-jV-tosyl-a-ketoenamines yield stereospecific-ally on irradiation a-keto azetidinones. Branched N-alkyl substituents suffer desulphona-tion and intramolecular aryl migration to give 2-amino-3-aryl-2-cyclohexenones333 (equation 252). 

Reaction of a-ketoenamines with a series of cyclic and acyclic nitroolefins gave aminocyclopentene derivatives with high diastereoselectivity, as products of kinetic control instead of the expected 1,2-oxazine N-oxides (see Section III.D.2)45,46. For example, ketoenamine 62 when reacted with cyclic nitroalkene 61 afforded 65 as a single diastereoisomer46, first through the dipolar intermediate 63 and later through the betaine-type intermediate 64. Hydrolysis of this enamine furnished the cyclopentanone derivative 66, also as a single diastereoisomer (equation 11). 

Generation of a-ketoenamines (Table 8, entry 8) [456] Spivey et al. [456] performed a pyrazole synthesis with a polymer-supported acetophenone and a germanium-based traceless linker. The support-bound acetophenone was allowed to react with dimethylformamide dimethyl acetal (Bredereck s reagent) [498]. Subsequent reaction of the resulting a-ketoenamine with aryl hydrazine hydrochlorides gave the pyrazoles. 

According to Pitacco, Valentin and coworkers secondary ketoenamines react generally with nitroolehns to give alkyl- and aryl-substituted tetrahydroindole-7-ones under thermodynamic control in good yield without any catalyst, if the a-ketoenamine is an N-alkyl derivative. The course of the reaction depends on the substituents and the conditions which result in different cleavage or rearrangement reactions. In the case of a-nitrostilbene a Michael adduct is obtained in low yield. If, however, for example, 1-nitrocyclopentene is used in the reaction with iV-t-butylenaminone under kinetic control, an unstable [4 -i- 2]cycloadduct can be isolated. The reaction clearly demonstrates the concurrence of Michael addition and subsequent cyclization to 7-indolones... 

The cyclization of aromatic a-ketoenamines 284 with electrophilic diazenes 285 at 5-20 °C in ethanol furnishes... 

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