2.4- Dimethylpyrrole

2 5-Dimethylpyrrole (II) is obtained by heating acetonylacetone (I) with ammonium carbonate at 100°  

In a 250 ml. conical flask, fitted with an air condenser of wide bore, place 50 g. (51 -5 ml.) of acetonylacetone (see Section V,9, Note 2) and 100 g. of ammonium carbonate (lump form). Heat the mixture in an oil bath at 100° until effervescence stops (60-90 minutes) some ammonium carbonate (or carbamate) sublimes into the condenser and this must be pushed back into the reaction mixture by means of a stout glass rod. Replace the air condenser by a Liebig s condenser with wide bore inner tube and reflux the mixture gently (bath temperature, 115°) for a further 30 minutes dissolve the solid which has sublimed into the condenser in about 5 ml. of hot water and return the solution to the reaction mixture. 

The preparation of 2 4-dimethyl-3 5-dicarbethoxypyrrole (II) is an example of the Knorr synthesis of pyrrole derivatives, involving the reaction of an -aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In the present synthesis from ethyl acetoacetate (I) may be represented as follows  

A solution of 270 g. (4.8 moles) of potassium hydroxide in 150 cc. of water is prepared in a 3-I. round-bottomed flask, 120 g. (0.5 mole) of crude 2,4-dimethyl-3,5-dicarbethoxypyrrole (p. 17) and a pinch of sand are added, and the whole is mixed thoroughly by shaking. The flask is fitted with a reflux condenser, and the mixture is heated in an oil bath at 130° for two to three hours with occasional shaking until the thick paste has become partially liquefied owing to the formation of dimethyl- 

The flask is next fitted for distillation with superheated steam and with a separatory funnel for the introduction of water into the center of the flask. A 3-I. round-bottomed flask fitted with a vertical condenser is used as a receiver, being connected directly to the inclined condenser from the distillation flask (Org. Syn. Coll. Vol. 1, 467, Fig. 24). The temperature of the oil bath is raised to 160° and superheated steam at 220-250° is introduced. The temperature of the oil bath is then gradually raised to 200°. 

If the contents of the flask cake or become semi-solid, the temperature of the oil bath should be lowered and the rate of flow of superheated steam gradually decreased. 

There is practically no fore-run, but if repeated or larger batches are made it is possible to obtain about 2 g. more of product per run from the higher-boiling fractions. If recrystallized ester is used a higher yield of dimethylpyrrole with less high-boiling products is obtained but the over-all yield is lower. 

4-Dimethylpyrrole is very readily oxidized in the air to a red resinous substance. If it is not used immediately, it should be stored under nitrogen or sealed in a glass vial under a vacuum. 

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Phosphoryl chloride Carbon disulflde, A,A-dimethylformamide, 2,5-dimethylpyrrole, 2,6-dimethyl-pyridine 1-oxide, dimethylsulfoxide, water, zinc... 

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). 

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

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... 

The Reimer-Tiemann reaction has also been used to formylate 2,5-dimethylpyrrole and its iV-methyl derivative and indoles having methyl, methoxyl, and phenyl substituents. Significantly, 3-methylindole gave only 3-chloro-4-methylquinoline. ... 

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)]. 

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]. 

Reaction of lithium 2,5-dimethylpyrrolate ion with [RhCl(CO)2]2 leads to formation of 84 (88PAC1193 90P1503). This is the first example of the mixed mode, when the ti N) and ti (C=C) coordination are realized simultaneously. Nucleophilic addition of triphenylphosphine and triphenylarsine gives 85 (E = P, As). The iridium analogs of 84 and 85 have also been synthesized. 

Aminomethylated V-aryl- and V-azaheteroaryl-2,5-dimethylpyrroles, compounds with potential biological activity 95F431. 

The failure of 2,5-dimethylpyrrole to dimerize is simple to understand. It is, however, difficult to understand why 2,4- and 3,4-di-methylpyrrole do not form simple dimers. ... 

Methylindole is, however, incorporated into mixed dimers and trimers. It thus reacts with indole and with skatole to form mixed dimers, and 2 moles react with 1 mole of indole for form a mixed trimcr. Likewise indole forms a dimer with 1,2-dimethylindole, 2-phenylindole, and even with 2,5-dimethylpyrrole, ... 

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). 

Diketohexane 1487 reacts with HMDS 2 in the presence of either CF3SO3H [41] or alumina [43] to give 2,5-dimethylpyrrole 1494 in 81% yield. The analogous reaction of the diketone 1495 with HMDS 2/AI2O3 furnishes the aza-prostacyclin derivative 1496 in 80% yield [44] (Scheme 9.25). 

Triflic acid (0.032 g) is added through a septum to a stirred mixture of 2,5-hex-andione 1487 (1.95 g, 0.017 mol) and HMDS 2 (7.4 mb, 0.035 mol) whereupon an exothermic reaction results and hexamethyldisiloxane 7 is removed by distillation through a short-path distillation head. When the reaction subsides (15 min) 81% pure 2,5-dimethylpyrrole 1494, b.p. 165 °C, is isolated by distillation [41]. 

Roskamp reported29 a similar intramolecular Diels-Alder reaction accelerated by silica gel saturated with water. The reaction led to the ready construction of the 11-oxabicyclo [6,2,1] ring systems (Eq. 12.4). The intramolecular Diels-Alder reaction has also been investigated by Keay.30 The Diels-Alder reaction of 2,5-dimethylpyrrole derivatives with dimethyl acetylenedicarboxylate in water generated the corresponding cyclization products.31... 

Varying ratios of the ligands 7V-(2-thiophenyl)-2,5-dimethylpyrrole and V-methylimidazole were used to form tetrahedral zinc complexes with S4, S3N, and S2N2 coordination spheres. X-ray structural analyses and IR spectra were recorded for all compounds and the relevance to zinc finger proteins was discussed. The comparison to cobalt and cadmium structures showed only minor differences, supporting the theory that changes on substituting these metals into zinc proteins would be minor.538... 

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. 

All of this structural work is backed up by total synthesis, which will be developed later. These syntheses often produce mixtures of cis-trans isomers. The natural products have a trans configuration and have the longest GC retention times. This attribution is based on an analogy with the hydrogenation of 2,5-dimethylpyrrole. 

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... 

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