1.6- Dioxo compounds synthesis

The usefulness of the Knorr synthesis arises from the fact that 1,3-dioxo compounds and a-aminoketones are much more easily accessible in large quantities than rational 1,4-difunctional precursors. Such practical syntheses are known for several important hetero-cycles. They are usually limited to certain substitution patterns of the target molecules. 

Altenbach, H.-J. and Kroff, R., p,e-Dioxophosphonates by reductive nucleophilic acylation of 1,3-dioxo compounds facile synthesis of jasmone, Angew. Chem., Int. Ed. Engl., 21, 371, 1982. 

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). 

Hwu et al. have examined the dependence of the metal oxidant on the mode of reactivity in silicon-controlled allylation of 1,3-dioxo compounds [95JOC856]. The use of manganese(III) acetate furnished the dihydrofuran product 22 only. On the other hand, use of cerium(IV) nitrate resulted in the formation of both acyclic (23) as well as the cyclized compound, with the product distribution dependent on the nature of the allylsilane. Facile synthesis of dihydrofurans by the cerium(IV) mediated oxidative addition of 1,3-dicarbonyl compounds to cyclic and acyclic alkenes has also been reported [95JCS(P1)187]. 

A few less traditional approaches to the synthesis of pyrrolo[2,3-<7]pyrimidines are worthy of note. Ketene 5,A-acetals (136) serve as convenient precursors to pyrrolopyrimidines which are reduced in the pyrrole ring (137) (Equation (47)). Heating compound (136) in a 1 2 ratio with arylisothiocyanates affords the dithio products (137 X = S) <83S225>, whilst similar treatment with arylisocyanates leads to the dioxo compounds (137 X = O) <85CPB4299>. 

Azole approach. 2,3-Dialkylthiazolium salts (411) where the a-carbon atoms carry at least two hydrogens can be made to condense with 1,2-dioxo compounds to form thiazolo[3,2-a]pyridines. A diketone or an oxoaldehyde will yield the cation (412) (69AG(E)74). Related is the condensation between a 2-oxo ester and a 2-alkylthiazole as in the synthesis of the 5-lactam (413) (74JPR684). 

Bisoxiranes can be prepared from dioxo compounds. With geminal chloromethyl-allyllithium the synthesis of new a-vinyl tri- and tetrasubstituted oxiranes has been developed (Eq. 93). ... 

Some forty years ago, Regitz et al. reported synthesis of vicinal triketone compounds from 2-diazo 1,3-dioxo-compounds using oxygen-halogen-insertion chemistry provided by ferf-butyl hypochlorite in formic acid. However, no analogous reaction for phosphorus compounds, in particular 2-diazo 1,3-diphos-phono substrates, had been previously described. 

Only two procedures are known for direct synthesis of the 2-pyrazolin-4-one ring system and one of these has been used very little. The chief method employed has been cyclization of the 1-arylhydrazone of 3-substituted-l,2-dioxo compounds (eq. 242) using basic cyclizing... 

The most carefully studied reductive approach concerned the preparation of dioxo compounds 59 from the propionic acids 58. The best reducing agent for this synthesis was found to be alkaline sodium borohydride. ... 

Cyclopenten-l-ol, l,3-dimethyl-2-(7-methyl-3,7-tridecadien-ll-ynyl), , )-, 91-92, 279-280 2-Cyclopenten-1 -one, 3-methyl-2-(2-pentenyl)-, (Z)- (fasmone) synthesis, 29 2-Cyclopenten-l-ones syntheses by cyclizations from 1,4-dioxo compounds, 69, 79 from 5-nitro-l,3-diones, 81 Cyclophanes of porphyrins, 253 meta-Cyclophanes, 38, 338 pora-Cyciophanes = tricyclo[8.2.2.24,7]hexadeca-4,6,10,12,13,15-hexaenes synth., 38-39 Cyclopropane derivs. See Carbocycles, 3-membered... 

Dioxo-compounds ox. cleavage, 137 synthesis via l-cyclobutene-l,2-diol derivs.,... 

Dioxo compounds cyclohexenones from, 71—73 reductive cyclization of, 41 synthesis of, 71-73... 

As an example of a steroid total synthesis, the industrial procedure used to make norgestrel, the gestagen used in many contraceptives, is sketched here. Its basis is the Torgov reaction, a variation of the Robinson annelation, which mns essentially neutral media. The carbanion of 1,3-dioxo compounds adds to allylic alcohols, e.g., 2-ethylcyclopentanol-1,3-dione, under weakly basic conditions. Both the dione and the styrene double bond are stable under these conditions. Regio- and stereoselective microbial reduction of one of the keto groups, acid-... 

Various modifications of this approach are demonstrated by the synthesis of condensed 1,2,4-triazines from 1,2-dioxo compounds and ortAo-amino derivatives of A -aminoazoles or A -aminoazines (Schemes 139-141) <1997J(P1)1829, 2000M487, 2001CPH77, 2002JC0419>. 

Oxidation of the hexahydro to tetrahydro derivatives was mentioned in connection with the synthesis of 3,5-dioxo-l,2,4-triazines (e.g., Section II,B,2,a). The reverse procedure, hydrogenation of the tetrahydro derivatives, was used with 6-azauracil, 6-azathymine, and their iV-methyl derivatives. With all these compounds hydrogenation proceeds smoothly in the presence of Adams catalyst. Only the hydrogenation of l-methyl-6-azathymine was not successful. ... 

Pyrrolo[ 1,2-c]oxazolc itself was used for further elaboration of more complex molecules. The main members of this family that are used as intermediates in organic synthesis are the 3-oxo and 5-oxo perhydro derivatives. One can find also a number of 1,3-dioxo, 3,5-dioxo, 3,7-dioxo, and 5,7-dioxo perhydropyrrolo[l,2-r ]oxazoles that were prepared and/ or converted into another valuable compounds. 

Hydrazination of 4-aryl-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine (66) also affords a rearranged product, 4-amino-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (81JHC953). This replacement of the A-aryl group by the N-amino group requires the intermediacy of the ring-opened compound 67. This intermediate could be isolated under mild conditions and its structure was proven by an independent synthesis. From this structure it can be concluded unequivocally that the ring transformation involves initial addition of the hydrazine at C-5 and not at C-3 (Scheme III.37). 

This paper traces in some detail the path which led to the discovery of a new class of herbicides, the 2-(5-oxo-2-imidazolin-2-yl)arylcarboxylates. The journey started when it was found that a phthalimide, a-isopropyl-a-methyl-l,3-dioxo-2-isoindoline-acetamide, had sufficient herbicidal activity to warrant further synthesis effort. This work led to a series of analogs essentially devoid of herbicidal activity yet possessing interesting plant growth regulating effects. Further chemical modifications resulted in the synthesis of two new groups of compounds, imidazoisoindolediones and dihydro-imidazoisoindolediones, and the return of herbicidal activity. The imidazoisoindolediones were in turn transformed into o-(5-oxo-imidazo-lin-2-yl)benzoates, the first members of a very interesting new class of herbicides. 

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