Enaminones cyclic—

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... 

Another example of halogen-atom transfer by CPO is the vinylic halogenation of cyclic enaminones and enamines (Eq. 10, Table 11). 

Enaminone 128 (Scheme 33) is obtained, together with an isomeric indo-lizine derivative, by flash vacuum thermolysis of aminomethylene Meldrum s acid derivative through intermediate ketene and delocalized azomethine ylide (85TL833). The thermally induced cyclization of semi-cyclic dienamines to afford, for instance, tricyclic 129 is also believed to start with an azomethine ylide (97JOC7744) the p-chlorophenyl substituent is essential for the reaction. Unstabilized ylide 130, on the other hand, is generated from pipecolinic acid and /1-phenylcinnamaldehyde by the decarboxylation method target base 131 is formed by 1,7-electrocycliza-tion and [l,5]-hydrogen shift (99J(P1)2605). 

Triazines are generally more reactive in [2 + 4] cycloaddition in comparison with 1,2,3-tria-zines. The wide variety of dienophiles can be employed enamines, enaminones, vinyl silyl ethers, vinyl thioethers, cyclic ketene jV,O-acetals, /V-phenylmaleimide, 6-dimethylaminopentafulvene, 2-alkylidene-imidazolidines (cychc ketene aminals), cyclic vinyl ethers, arynes, benzocyclopropene, acetylenes, and alkenes like ethylene, (Z)-but-2-ene, cyclopentene, cyclooctene and bicyclo[2.2.1]hept-2-ene, hexa-1,5-diene, cycloocta-1,5-diene, diallyl ether, cyclododeca-l,5,9-triene,... 

An improved synthesis of myrtine (23) from ( )-pelletierine (21) has been reported (Scheme 3) (c/. Vol. 9, p. 71). Stereospecific addition of methyl-magnesium iodide to the cyclic enaminone (22) gave ( )-myrtine, which was converted into natural (+)-myrtine by resolution with (-)-tartaric acid.31... 

Ring closure of enamines and acid chlorides39, esters601 or nitriles (equation 40) or intramolecular alkylation of enaminone602,603 (equation 41) are general methods for the preparation of cyclic enaminones. 

Greenhill and coworkers have shown that the reaction of cyclic enaminones with isothiocyanates can be controlled regioselectively to attack the nitrogen or the / -carbon according to the reaction conditions8. Surprisingly, a heterocyclic spiro-product formed by reaction with two isothiocyanate molecules is observed in one case (equation 4). (equation 4). 

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... 

The normal Hantzsch variant can be extended to the synthesis of acridine derivatives by using cyclic enaminones26-28 (equation 18). Similar, partly aromatic acridones are obtained in high yield from jV-(0-hydroxymethylphenyl)enaminones derived from dime-done29. 

Cyclic iV-quinonylenaminones have been treated with trifluoroacetic acid/trifluoroace-tic anhydride in order to obtain cyclization to carbazole derivatives. However, the result was a nucleophilic ( ) attack by trifluoroacetate at the enaminone a-methylene group. Cyclization gave a phenoxazinone derivative49 (equation 31). By intramolecular acylation 4-quinolones are also available50 (equation 32). 

Acylations of enaminones is a well known process1. However, the reaction of trichloroacetyl chloride interestingly differs from the normal reaction of acyl halides in yielding pyrans by attack of the a-methyl group of enaminone (equation 38)56. This gives a new access to cyclic and acyclic compounds by using various transformations. 

If the -position is blocked as in the case of cyclic enaminones, the acylation proceeds on nitrogen. The corresponding amide is isolable, and the spirocyclization to 2-indolone derivatives can be later accomplished in good yield (equation 40). 

Condensation reaction of an enaminone with 2-aminopropene-l,l,3-tricarbonitrile leads to a low yield of 2-dicyanomethylene-3-cyano-dihydropyridines, which are used as synthons for 1,6-naphthyridines63 (equation 45). Cyclic enaminones react similarly with malononitrile to give isoquinoline derivatives (equation 46). 

Benzoylacrylonitrile and a cyclic enaminone simply react to give 2-phenylquinolone in good yield. The cyano group is lost as a hydrogen cyanide80 (equation 56). 

Another type of cyclic enaminones was used for stereospecific synthesis of cyclohexanone derivatives by addition of a,/ -unsaturated carbonyl compounds83 (equation 59). 

Simple tertiary enaminones derived from acetylacetone and benzoylacetone react with acryloyl chloride to yield carbocyclic derivatives. The reaction proceeds via an initial Michael addition of the enaminone / -carbon to the enone107 (equation 76). Analogous behavior of cyclic enaminones leads, according to ring size, to tetrahydroindole, quinoline and benzazepine derivatives108 (equation 77). 

Selective specific alkylations at the a-methylene group of enaminones are of interest because of their preparative value. The alkylation of cyclic enaminones involving deprotonation with w-butyllithium is called y-alkylation154 (equation 102). Similarly lithium diisopropylamide in THF ( — 78°C) can be also used155. 

Oxo-/ -carbolines have been also synthesized in 21-31% yield by using arylpalladi-um complexes168. Ten years after the introduction of the method this palladium-catalysed cyclization of cyclic and acyclic Af-(2-iodophenyl)-substituted enaminones was... 

Cyclic enaminones react with diacyl peroxides to yield products of monoacyloxylation, which subsequently give cyclohexadienones199 (equation 140). 

Acetamides of cyclic enaminones cyclized upon treatment with tributylstannane and AIBN to give spirocyclic compounds201 (equation 141). 

In a recent publication, amidine derivatives of a cyclic enaminone are used as the heterodiene component in a Diels-Alder reaction with diethyl maleate to yield 5-quinolones203 (equation 145). 

In some cases an intramolecular arylation (Section A.l.i, f, equations 85 and 107) is problematic. Cyclic Af-(2-bromophenylethylenaminones instead of benzazepines with LiNEt2 yield indolines. Photolysis seems to be a good alternative method. A photolytic reaction of the same reagents leads to the desired benzazepines in high yield204-207 (equation 146). Carbazoles and phenanthridines can also be obtained by photocycliza-tion of brominated N-phenyl, N-benzyl derivatives of cyclic enaminones in yields similar to those in the base promoted cyclization (see equations 84, 106 and 107). 

A-Vinylenaminones are photochemically transformed to 3-acylpyrroles or indolones (equation 148). However, acyclic enaminones give low yield and cyclic enaminones yield mixtures of indoline and indole derivatives210. 

A method was also developed for the synthesis of phenols. Condensation of different cyclic and acyclic tertiary enaminones and 3-oxoglutarate affords substituted phenols, including condensed systems2110 (equation 150). 

Attack of nucleophiles at the a-position of the enaminone predominates, leading to Michael addition which mostly results in substituted, mainly cyclic end-products. Also observed are subsequent amine elimination and reactions at the carbonyl. Some initial reactions of nucleophilic reagents at the enaminone carbonyl carbon are known. Enaminones are often better starting materials for several reactions than the corresponding dicarbonyls. As a result, a-aminomethylene ketones act as 1,3-biselectrophiles. Due to their combined electrophilic and nucleophilic properties, enaminones act as 1,3-bisnucleophiles as well. The assumed first step in the following reactions is the one used for classification of the reactions. In addition, enaminones are used as heterodienes in 4 + 2-cycloaddition mostly with electron-deficient dienophiles. 

We have studied the reaction of similar cyclic -substituted enaminones which yielded indolones when the reaction was carried out in acetic acid and the quinones had lower oxidation potential, thus preventing prior oxidation of the enaminones. Secondary aminomethylene derivatives of cyclopentanone, cyclohexanone and cycloheptanone reacted with the quinones to presumably form intermediate spiro compounds, as a consequence of normal enaminone chemistry. However, this was unexpectedly followed by rearrangement with ring expansion to indolones (equation 158). In this way carba-zoles, cycloheptindoles and cyclooctindoles can be obtained by a simple entry to this class of indoles, although partially in low yields222-224. Due to their bifunction-ality the produced indol-2-ones are versatile synthons for fused heterocycles (e.g. triazepino- and pyrazino-carbazoles) which become easily accessible225,226. 

Aminoacrolein itself reacts as a primary enaminone with cyclic ketones under forced conditions to give higher polymethylene pyridines232 (equation 163). 

An interesting feature is the ring contraction of cyclic enaminones. On bromination at the -position with subsequent hydrolysis of the iminium ion formed, cyclization of the acyclic intermediate to the resulting pyrrolidine- or piperidine-2-carboxaldehydes proceeds in excellent yield245 (equation 177). The enaminone a-carbon is formally functionalized in this way to an aldehyde group via reduction of the size of the ring. 

Theoretical interpretation and a brief review of literature concerning the chemistry of sulphene addition to open-chain, cyclic or heterocyclic enaminones have been given269. 

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 the case of cyclic tertiary enaminones as dienophiles in the reaction with nitroalk-enes as heterodienes, [4 + 2]-cycloaddition yields tetrahydrobenzo >][l,2]oxazin-8-ones nearly quantitatively. Heating in aprotic solvents affords substituted diaster-eoisomeric pentalenones by ring contraction of the six-membered ring326 (equation 244). 

In a similar manner the reaction of tertiary enaminones and cyclic nitroolefins is used for the synthesis of a triquinan in high yield327 (equation 245). 

Cyclic, fully conjugated enaminones underwent mono- and bis-oxyacylation by dia-roylperoxides54 (Scheme 37). 

Lithium aluminium hydride is also capable of reducing N-silyloxy enamines153. Active methylene compounds such as open-chain and cyclic ketones can be converted into the corresponding Mannich base through the intermediacy of enaminones, which are reduced by LiAlH4154 (Scheme 108). 

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