Pyrrole Chemistry: Iv. The Preparation and Some Reactions of Brominated Pyrrole Derivatives

Abstract

IVIethyl 2-pyrrolecarboxylate and 2-pyrrolecarboxaldehyde have been brominated under a variety of conditions and the isomer ratios determined. The products have been identilied as the 4-bromo, 5-bromo, and 4,5-dibromo derivatives and their structures proved. I t has been sho~vn that the bromine group in these products is not easily displaced by nucleophiles although this has been accomplished with the cyanide ion. The bromine has been removed easily by catalytic hydrogenation.In our survey of the reactions of relatively simple pyrrole derivatives (1) it appeared likely that broinination might prove both useful and interesting. A selection of types of brominating agents including molecular bromine, the bromonium ion, and the bromine atom is available (2). In turn it might prove possible to replace the broinine group by others such as cyanide or methoxyl as has been done in the thiophene and furan series (3, 4, 5). The most satisfactory starting materials appeared t o be methyl 2-pyrrolecarboxylate and 2-pyrrolecarboxaldehyde. The electron-withdrawing groups would provide a 4-directing effect. Thus a mixture of 4-and 5-isomers would be formed (1, 6 ) which might be made to favor one or the other position by a choice of the type of brominating agent. In addition, both ester and aldehyde can be converted to the acid group which then might be removed by decarboxylation. Finally, the deactivation of an electronwithdrawing group would be necessary to allow the isolation of monobrominated products in reasonable yields (7). From the reaction products we isolated 4-bromo, 5-bromo, and 4,5-dibromo derivatives for both the 2-ester and the 2-aldehyde. A small amount of the 3,4,5-tribromo-2-ester (8) was also found in one reaction, i\4ethyl 4,5-dibroino-2-pyrrolecarboxylate (9) has been reported previously. ' Identification of the monobroininated-2-esters (I) was accomplished by a series of reactions. First, nucleophilic displacement of the bromine group was carried out using cuprous cyanide in hot dimethyl sulfoxide. The yields of methyl 4-and 5-cyano-2-pyrrolecarboxylate (11) were not good but in each case a single product was obtained and characterized. Then methyl 2-pyrrolecarboxylate was forinylated by the Vilsmeier-Haack technique (3) producing a mixture (111), containing mostly the 4-formyl-2-ester along with some of the 5-formyl-2-ester. Pinder (10) has formylated the corresponding ethyl ester but obtained a considerably greater proportion of 5-forinylation. Each formyl-2-ester was then subjected to two operations. First, it was oxidized (IV) and esterified (V) to the known methyl 2,5-or 2,4-pyrroledicarboxylate ( l l ) , thus proving the orientation of substituents. A second portion of each forn~yl-2-ester was converted to the oxime (VI), dehydrated t o the corresponding 4-or 5-cyano-2-ester and used for mixed melting point and comparison of infrared spectrum with the products (11) obtained above. Further

Chemical defenses of the Caribbean sponges Agelas wiedenmayeri and Agelas conifera

“…For studying the structure-activity relationship of the pyrrole part of bromopyrrole alkaloids, brominated pyrrole-2-carboxylic acid derivatives were either purchased commercially (9, 14-17, 19-22) or synthesized (10-13, 18) following procedures previously described by Bailey et al (1971) and Anderson & Lee (1965). Structures of the compounds were determined by mass spectrometry and NMR spectroscopy.…”

Five‐Membered Heterocycles: Pyrrole and Related Systems

“…Hence, in the early days, the availability of such pyrrole derivatives was severely limited, although syntheses of several relatively stable iodinated pyrroles, for example 2,3,4,5-tetraiodopyrrole [222], as well as some other bromo-or iodopyrroles featuring additional electron-withdrawing substituents were described [223,224]. An early study on the bromination of methyl pyrrole-2-carboxylate and pyrrole-2-carboxaldehyde under various conditions clearly demonstrated that formation of mixtures containing several halogenation products is a common course of many of these reactions, thus illustrating yet another complicating factor [225]. The labile 1-chloropyrrole, generated in 65-72% yield by chlorination of pyrrole with NaOCl, was shown to rearrange readily to give mixtures containing several species, such as 2-choro-and 3-chloropyrrole, when subjected to acidic conditions or heated in methanol [226].…”

Perspectives on the synthesis and use of ageladine A

“…The Pictet-Spengler reaction uses 2-acetyl-aminohistamine [8] and 4,5-dibromo-1-SEM-pyrrol-2-carb-aldehyde [9] synthesized in a two-step synthesis starting with the bromination of pyrrol-2-carbaldehyde 25,26 and protection with trimethylsilylethoxymethyl chloride (SEMCl) 15. . This protecting group revealed itself as the most stable during the subsequent reactions steps and makes the chromatographic procedures easier, compared to the Boc-group.…”