A N o v e l R o u t e t o 1 , 2 , 4 -t r i s u b s t i t u t e d P y r r o l e s Abstract: 2-(Acylmethylene)propanediol diacetates, which cyclize readily under acidic conditions to give furans (76-84%) react with primary amines under palladium catalysis to give 1,2,4-trisubstituted pyrroles in moderate to good yields (39-53%). When glycine methyl ester is used as the amine, substituted methyl pyrrol-1-ylacetates (31-82%) are obtained.Probably the best known access to furans and pyrroles is by the Paal-Knorr synthesis. 1 1,4-Dicarbonyl compounds are cyclized under acid catalysis and with dehydration to give furans; in the presence of primary amines or ammonium salts, the corresponding pyrroles are formed. By a similar mechanism, but under much milder conditions, furans are also formed under acid catalysis from a,b-unsaturated g-hydroxyketones of type 1 (Scheme 1). 2 Starting from readily available dihydroxyacetone diacetate 3, 3 we have extended a known access 4 to functionally substituted furans 6 and developed an analogous, yet palladiumcatalyzed reaction leading to pyrroles. Scheme 1 Furans from a,b-unsaturated g-hydroxyketonesIn this extension of the furan synthesis, a,b-unsaturated gacetoxyketones 5a-c which were obtained by HornerWadsworth-Emmons olefination of 1,3-diacetoxy-2-propanone (3) with b-ketophosphonates 4a-c in 62-83% yield, were used as precursors (Scheme 2, Table 1). 5 Upon treatment of the 3,3-bis(acetoxymethyl)-substituted enones 5 with hydrochloric acid in methanol at 50°C for 30-60 minutes, the corresponding 2-substituted 4-hydroxymethylfurans 6a-c were formed in 76-84% yield. 5 This reaction involves the hydrolysis of the two acetoxy moieties to give the bisallylic alcohol which, under the acidic conditions, forms the furan. Formation of the 4-fluorophenyl-substituted furan 6c proceeded much faster than the formation of the methyl-and ethyl-substituted furans 6a,b.In a first attempt to further extend the scope of this reaction to the synthesis of pyrroles, the simple addition of primary amines and ammonium salts to precursors 5a-c was tested under acidic and basic conditions. But no trace of a pyrrole could be detected in any case. Since pyrroles can only be formed after nucleophilic substitution of at least one of the allylic acetoxy groups in 5 by an amine, and this kind of substitution is generally catalyzed by palladium(0), 6,7 compounds 5a,c were treated with two equivalents of benzylamine and 5 mol% of tetrakis(triphenylphosphine)palladium in refluxing tetrahydrofuran to give the desired pyrroles 7a,c as orange oils in 53 and 39% yield, respectively (Scheme 3, Table 2). 5

5‐Methylene‐2‐oxo[1,3,2]dioxathiane (2) was obtained in 91% yield from 2‐methylenepropane‐1,3‐diol (1) and thionyl chloride. The cyclic sulfite 2 reacts with a variety of nucleophiles to give formally monosubstituted products 3 of the diol 1 in 62−77% yield. Oxidation of 2 with RuCl3/NaIO4 yields the diprotected tetraol 5‐(hydroxymethyl)‐2,2‐dioxo[1,3,2]dioxathian‐5‐ol (7) in 86% yield, which can be used to easily access tetrafunctional derivatives of 2‐(hydroxymethyl)propane‐1,2,3‐triol (isoerythritol); for example, acetylation with acetic anhydride furnishes in 96% yield the primary acetate 11, which reacts with potassium cyanide and sodium azide to give the 2‐cyano‐ and 2‐(azidomethyl)propane‐1,2,3‐triol monoacetates 12a,b (78 and 82% yield, respectively). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

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Alcohols Alcohols P 0110Easy Access to Derivatives of 2-(Hydroxymethyl)propane-1,2,3-triol (Isoerythritol) with up to Four Separately Addressable Functionalities. -Cyclic sulfite (II) is oxidized by ruthenium tetroxide to give (VIII) which is protected with acetic anhydride. The resulting acetate can be treated with various nucleophiles leading to the corresponding monosubstitution products and after hydrolysis and aqueous work-up monoacetylated triols are isolated. Nucleophilic ring opening results in formation of open-chain sulfates. -(FRIEDRICH, M.; SAVCHENKO, A. I.; WAECHTLER, A.; DE MEIJERE*, A.; Eur.

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