Cyclization aminoketone

Danishafsky and Feldman (21) have shown that the cyclization of the aminoketone (28) led to the internal enamine (29), which lacks the steric interaction of the type existent in the enamines of 2-alkycyclohexanones. In this case, the tetrasubstituted isomer was favored over the trisubstituted one by a factor of 4 1, which may be ascribed to the double bond being in the exo position in the latter case. 

A similar microwave-assisted cyclization in the presence of ammonium acetate of an a-ketoamide, obtained by acylation of an a-aminoketone, was recently described for the synthesis of the antifungal agent Nortopsedin D [46]. The problem of the instabiUty of the a-amino ketones was successfully resolved by in situ acylation of the amine derived from Staudinger reaction of the azide 50 with a phosphine (Scheme 16). This ketoamide was... 

CINNOLINES AND QUINOXALINES Replacement of a methine in oxolinic acid (46) by nitrogen is apparently consistent with retention of antibacterial activity. One approach begins with reduction of nitroacetophenone 144 to afford the corresponding aminoketone (145). Treatment of this intermediate with nitrous acid leads to the diazonium salt the diazonium group condenses with the ketone methylene group (as its enol form) to lead to the cyclized product, cinnoline 147. Bromination proceeds at the position adjacent the enol grouping (148) ... 

This approach to the five-membered pyrrole ring reacts an a-aminoketone with a P-ketoester. The mechanism will probably involve imine formation then cyclization via an aldol-type reaction using the enamine nucleophile. Dehydration leads to the pyrrole. Only the key parts of this sequence are shown below. 

Hydrogenolysis of the oxazoline 95 also led to cyclization and reduction of the resulting aminoketone, forming the pyrrolidine 96. The pyrrolidine was transformed into (-i-)-preussin (2), which was obtained in ten steps from L-iV-benzoylphenylalaninol, with an overall yield of 13%. 

Condensation of an aminoketone with urea leads to the formation of a quinazolone by incorporation of carbonyl carbon and one amino group. Thus reaction of the aminobenzophenone (84-1) with urea can be rationalized by assuming the initial formation of the urea exchange intermediate (84-2). Cyclization will then give fluproquazone (84-3) [94], a nonopioid analgesic that shows NSAID-like activity in the absence of a typical acidic function. 

The problems involved are exemplified here by Knorr s pyrrole synthesis (A. Gossauer, 1974). It has been known for almost a century that a-aminoketones (C2N components) react with 1,3-dioxo compounds (C2 components) to form pyrroles (C4N-heterocycles). A side-reaction is the cyclodimerization of the a-aminoketones to yield dihydropyrazines (C4Nj), but this can be minimized by keeping the concentration of the ar-aminoketone low relative to the 1,3-dioxo compound. The first step in Knorr s pyrrole synthesis is the formation of an imine. This depends critically on the pH of the solution. The nucleophilicity of the amine is lost on protonation, whereas the carbonyl groups are activated by protons. An optimum is found around pH 5, where yields of about 60% can be reached. At pH 4 or 6 the yield of the pyrrole may approach zero. The ester groups of /7-keto esters do not react with the amine under these conditions. If a more reactive 1,3-diketone is used, it has to be symmetrical, otherwise mixtures of two different imines are obtained. The imine formed rearranges to an enamine, which cyclizes and dehydrates to yield a 3-acylpyrrole as the normal Knorr product (A. Gossauer, 1974 G.W. Kenner, 1973 B). 

The time-proven approaches for the synthesis of pyrroles and more elaborate systems have been thoroughly reviewed in the literature. Our focus is drawn to the Knorr synthesis of pyrroles as the [3 + 2] component condensation-type approach which serves as the foundation for the methodology discussed in this chapter.3 The classic reaction entails the reaction of an a-aminoketone with a P-dicarbonyl compound (Eq. 1). The likely intermediate is a P-aminoenone, which undergoes an acid-catalyzed internal cyclization reaction leading to the pyrrole ring. A variation of this process involves the condensation of a-aminoesters and... 

The cyclization to 7 proceeds with high diastereoselectivity. Furthermore, from a mechanistic point of view it is noteworthy that, if enantio-merically pure aminoketones 4 are used, only one enantiomer of the cyclopropanes is obtained [35e]. Obviously, the biradicals 6 are so... 

Hydroxy aldehydes or ketones normally exist in equilibrium with the corresponding 2-hydroxytetrahydrofurans, which afford 2,3-dihydrofurans on dehydration. Similarly, 7-aminoketones spontaneously yield pyrrolines. From a mechanistic viewpoint the-initial cyclizations may be regarded as being initiated by nucleophilic attack of the heteroatom upon the carbonyl group. While such reactions occur with facility, their synthetic applicability is largely determined by the accessibility of appropriate precursors. A selection of examples of this type of ring closure is provided in Scheme 12. 

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