1.2- Dioxo compounds pyrroles

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). 

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>. 

Potassium tert-butoxide Pyrroles from a-dioxo compounds... 

Methyl 3-acyl-l-diphenylmethyleneamino-4,5-dioxo-4,5-dihydro-l//-pyrrole-2-carboxylates 489 are formed from 488 and oxalyl chloride in good yields. Preparative thermolysis of these compounds at 130-140°C gives mixtures of dipyrazolo[l,2- l,2- [l,2,4,5]tetrazines 491 as major products and pyrazoles 492 as minor hydrolytic by-products. The intermediacy of mesoionic compound 490 is expected (Scheme 83) <2004T5319>. 

The pyrrole nucleus is commonly found in biologically active lead compounds and designed analogs, and two out of many recently published examples will be mentioned here. The pyrrole core structures of roseophilin and prodigiosin have been studied as protein tyrosine phosphatase inhibitors <04CBC1575>. A new class of 2-vinylpyrroles, 6-pyrrolyl-2,4-dioxo-5-hexenoic acids, were found to be active HIV-1 integrase inhibitors <04BMCL1745>. 

---