Pyrrole 2,5-dimethylpyrrole

Ring openings of pyrrole commonly occur at the carbon—nitrogen bond. Treatment of pyrrole or 2,5-dimethylpyrrole [625-84-3] (23, R = CH3) with hydroxjlamine leads to ring opening and formation of dioximes (31) (39). 

The most convenient laboratory method for the preparation of 2,4-dimethyl-5-carbethoxypyrrole is that given above. A cheaper method of obtaining large quantities consists in the partial hydrolysis of 2,4-dimethyl-3,5-dicarbethoxypyrrole with sulfuric acid, followed by decarboxylation. The ester has been obtained also by the alcoholysis of 5-trichloroaceto-2,4-dimethyl-pyrrole in the presence of sodium ethylate. The free acid has been obtained fronii-[2,4-dimethylpyrrole-5]-2,4-dimethylpyrrole-5-carboxylic acid and from 2,4-dimethylpyrrole-5-aldehyde. ... 

Fluormated pyrroles are obtained from 2,5-dimethylpyrrole by reductive alkylation with perfluoroaldehyde hydrates [174] (equation 149)... 

Knorr discovered that treatment of ethyl a-oximinoacetoacetate (7) and ethyl acetoacetate (8) with zinc and acetic acid affords 2,4-dicarboethoxy-3,5-dimethylpyrrole (9). Extensive modifications of this reaction over the past 100 years have elevated the Knorr pyrrole synthesis to one of exceptional generality and versatility. 

Other PK variations include microwave conditions, solid-phase synthesis, and the fixation of atmospheric nitrogen as the nitrogen source (27—>28). Hexamethyldisilazane (HMDS) is also an excellent ammonia equivalent in the PK synthesis. For example, 2,5-hexanedione and HMDS on alumina gives 2,5-dimethylpyrrole in 81% yield at room temperature. Ammonium formate can be used as a nitrogen source in the PK synthesis of pyrroles from l,4-diaryl-2-butene-l,4-diones under Pd-catalyzed transfer hydrogenation conditions. 

Tetramethylisoindolenine (50) is obtained as an unstable, crystalline solid from the reaction of 2,5-hexanedione with 2,5-dimethylpyrrole in the presence of sulfuric acid. Treatment of the same diketone with ammonium sulfate also affords this isoindolenine. NMR measurements in deuteriochloroform indicate that a small amount of 1,3,4,7-tetramethylisoindole (51) is present in equilibrium with the isoindolenine. This same isoindole was postulated as an intermediate in the reductive self-condensation of 2,5-dimethyl-pyrrole (52) which affords a mixture of cis- and lwMs-l,3,4,7-tetra-methylisoindolines (53 and 54). Hydrolytic opening of the... 

A variant of the Reimer-Tiemann reaction, using chloroform or bromoform with ethanohc sodium ethoxide, has been apphed (mainly by Plancher and co-workers) to certain pyrroles and indoles with interesting results. Thus Bocchi has shown that 2,5-dimethylpyrrole gave 3-halogeno-2,6-dimethylpyridine, and 2,4-dimethylpyrrole with bromoform gave two isomeric bromodimethylpyridines [Eq. (11)]. 

The latter reaction has been repeatedly misquoted (e.g. ref. 50) as involving 2,3-dimethylpyrrole, but the Reimer-Tiemann reaction of this pyrrole has not been investigated. In this case the methyl groups should activate the 2,3-bond sufficiently to make the 3-halogeno-2,4-dimethylpyridine the major—if not the sole— product. 

Cobalt complex 83 was obtained by the reaction of [CpCo(SMe2)3l2(BF4)2 with pentamethylpyrrole [88AG(E)579]. Full cobalt sandwich of 2,5-di-terr-butyl-pyrrole is also known [91JCS(CC)1368]. Meanwhile, attempts to synthesize other pyrrolyl complexes of cobalt, (Ti -2,5-dimethylpyrrole)cobalttricarbonyl and the 3,4-dimethyl analog, have been unsuccessful [87JOM(330)231]. 

As in the [22]porphyrin(3.1.3.1) series, the cyclohexene moieties being part of the bridges originate from the preparation of the dimers from dimethylpyrrole and a hydronaphthalene diketone by acid-catalyzed condensation. The synthetic approach developed by Franck2b has the advantage over the foregoing method that more stable conventional pyrroles and dipyrryl-methanes can be used to form the macrotetracycle in a stepwise manner. 

It has long been known that pyrroles can be used as coupling components (see, for example, Schofield, 1967, p. 76). More recently Butler and coworkers have studied the reactions of arenediazonium ions with pyrroles (Butler et al., 1977 Butler and Shepherd, 1978, 1980). 1-Methyl- and 2,5-dimethylpyrrole react with diazotized sulfanilic acid to give 12.34 and 12.35 respectively. The formation of 12.34 is in accordance with the a-positions in pyrrole being more susceptible to elec-... 

Besides the azo coupling reactions of 1-methyl- and 2,5-dimethylpyrrole with benzenediazonium-4-sulfonate mentioned above, Butler et al. (1977) synthesized almost all possible combination products of the unsubstituted and four 4-substituted benzenediazonium ions with pyrrole itself, with most isomeric mono-, di-, and trimethyl-pyrroles, and with 3-ethyl-2,4-dimethylpyrrole. These authors also investigated the kinetics of all these combinations (see Sec. 12.7). 

Poor stirring during formylation of 2,5-dimethylpyrrole with the preformed complex of dimethylformamide with phosphoryl chloride caused eruption of the flask contents. Reaction of the complex with a local excess of the pyrrole may have been involved. 

The large scale preparation of orthogonally protected pyrrole tricarboxylic acid derivatives (i.e., 92) was reported. A key step was the selective a-chlorination of a 2,4-dimethylpyrrole intermediate that was derived from the Knorr pyrrole synthesis. 

The chemical structure of 2,5-hexanedione suggested that it could react with lysine side-chain amino groups in proteins to form pyrroles (see Figure 2-7). In vitro experiments showed that this was, in fact, the case, and that the modified proteins can undergo secondary reactions to yield oxidized and polymeric products (DeCaprio et al. 1982 Graham et al. 1982). Oral administration of 2,5-hexanedione produced evidence that this process can take place in vivo as demonstrated by the detection of 2,5-dimethylpyrrole adducts in serum and axonal cytoskeletal proteins (DeCaprio and O Neill 1985). When a series of... 

Problem 20.5 Pyrroles, furans, and thiophenes are made by heating 1,4-dicarbonyl compounds with (NH4)2C0, P4O, and PjS, respectively. Which dicarbonyl compound is used to prepare (o) 3,4-dimethyl-furan. (h) 2,5-dimethylthiophene. (c) 2,3-dimethylpyrrole <... 

Pyrroles and furans also undergo the Gattermann aldehyde synthesis with HC1 and HCN, furan gives furfuraldehyde and 2-methylindole gives 2-methylindole-3-carboxaldehyde. The Houben-Hoesch ketone synthesis is also applicable to the preparation of acyl derivatives of furans and pyrroles, e.g. ethyl 2,4-dimethylpyrrole-3-carboxylate with MeCN and HC1 yields (81). 

The ion (97), acting as an electrophilic reagent, can also attack another molecule of the heterocyclic compound. Thiophene with benzaldehyde or chloral gives the dinuclear product (100 R = Ph, CC13). Pyrrole and furan react with acetone to form tetranuclear derivatives of type (101 Z = NH, O). Pyrroles with a single free position react analogously to thiophene e.g. two molecules of 3-ethoxycarbonyl-2,4-dimethylpyrrole with formaldehyde afford the dipyrromethane (102). 

In the pyrrole series, ester groups a to nitrogen are more readily hydrolyzed by alkali, but those in a (3 position more readily by acid. Thus, in compounds such as diethyl 2,4-dimethylpyrrole-3,5-dicarboxylate (360) either ethoxycarbonyl group may be selectively hydrolyzed and, if desired, subsequently eliminated by decarboxylation. 

Although the hydroxy group is a relatively poor leaving group, its base-catalyzed nucleophilic substitution by the mechanism shown in Scheme 69 accounts not only for the hydrogenolysis of the 3-hydroxymethylindoles, but also for their SN reactions with ethoxide ions, cyanide ions and with piperidine. Nucleophilic substitution on 2-hydroxymethyl-pyrroles is generally precluded by the faster formation of the bis(2-pyrrolyl)methanes, but the synthesis of 2-cyano-2-(2,5-dimethyl-3-pyrroIyl) propanes from 2,5-dimethylpyrrole, propanone and potassium cyanide probably results from an SN reaction of the cyanide ion upon the initially formed 3-pyrrolylcarbinol (81USP4248784). The formation of (294)... 

Condensation of formyl-pyrroles and -indoles with a wide range of other activated methylene compounds has been reported. These include, for example, hydantoin, which provides a useful synthetic route to tryptophane and j8- (pyrrolyl)alanines, thiohydantoin, rhodanine and AT-substituted barbituric acids (B-77MI30505, 79HC(25-3)357). Flash pyrolysis of the condensation product derived from 3-formyl-2,5-dimethylpyrrole with Meldrum s acid produces 6-hydroxy-2-methylindole, (440) — (441) (74AJC2605), whilst the analogous... 

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