2.4- Dimethylpyrrole-3-carboxylic acid

The structure of batrachotoxin was confirmed by a partial synthesis from batrachotoxinin A. This proved feasible using a mixed anhydride prepared from 2,4-dimethylpyrrole-3-carboxylic acid and ethyl chlorofor-mate (Scheme I). A variety of analogs of batrachotoxin were prepared in a similar manner. These compounds are documented in Table 4. A dihydro-batrachotoxin was prepared by sodium borohydride reduction (Scheme II) and apparently is subject to allylic rearrangement to other dihydroproducts 251). 

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. ... 

By means of oxidation of the initially formed 3,4-disubstituted 5-bromo-2-bromomethylpyrrole, bromine converted 3,4-disubstituted-2-methylpyr-roles and their 5-carboxylic acids into 5-bromo-5 -bromomethyl-2,2 -dipyrrolylmethanes. Similar reaction with sulfuryl chloride led to the analogous chloro species (77MI2). Whereas treatment of 2-aroyl-l,3-dimethylpyrrole-5-acetic esters with NBS brominated the vacant ring carbon, the related oxalate ester gave the 3-bromomethyl derivative (80JMC98). 

Pyrrole reacts with aryl isocyanates to give anilides of pyrrole-2-carboxylic acid. Pyrrole homologues behave similarly 2,4-dimethylpyrrole gives derivatives of 3,5-dimethylpyrrole-2-carboxylic acid, and 2,5-dimethylpyrrole reacts at the jS-position. The reactions are useful for characterizing simple pyrroles ... 

Fischer and Walach i showed that if Knorr s pyrrole is dissolved in concentrated sulphuric acid at 40° and the solution then poured on ice, 2-ethoxycarbonyl-3,5-dimethylpyrrole-4-carboxylic acid results. Probably, dissolution of the diester in concentrated sulphuric acid generates the acylium ion (77) evidence for this is the van t Hoff cryoscopic factor of 3 5 observed for such solutions a xhe process cannot be complete at the freezing point, for complete acylization would give s factor of 5. Acyli-zation 184 AacI > will be facilitated by electron-releasing substituents and will not be subject to steric factors. In the pyrrole series, a balance has to be struck between the facilitation caused by increasing alkyl substitution in the nucleus and the retardation which would accompany salt formation by... 

Pyrrole reacts with aqueous formaldehyde and secondary amines in the presence of acetic acid to afford, in some cases, mixtures of products derived from attack at the 2- and 2,5-positions. The disubstitution products can be obtained in very high yields at about room temperature for example, a 92% yield of 2,5-bis(piperidylmethyl)pyrrole is obtained using this method. The same procedure apparently does not yield a Mannich base with l-methylpyrrole, but the use of aqueous formaldehyde and dimethylamine hydrochloride at 60 °C results in the formation of the 2-substitution product in 73% yield. Even highly substituted pyrroles react. Thus, ethyl 4,5-dimethylpyrrole-2-carboxylate and ethyl 2,5-dimethylpyrrole-3-carboxylate both undergo C-aminoalkylation at the unsubstituted position in 45 and 68% yields, respectively, with dimethylamine and formaldehyde in ethanolic solution. A number of tri- and tetra-substituted 2-methylpyrroles have been investigated with the exception of Knorr s pyrrole all gave side-chain substituted products with formaldehyde and a secondary amine in acetic acid. ... 

A suspension of benzyl 2-acetoxymethyl-3-(2-methoxycarbonylethyl)-4-methyl-pyrrole-5-carboxylate and 3-acetyl-2,4-dimethylpyrrole in methanol treated with p-toluenesulfonic acid hydrate, and warmed 4 hrs. at 35 under Ng -> product. Y 91%. F. e., also tripyrranes, s. A. M. d A. Rodia Gonsalves, G. W. Kenner, and K. M. Smith, Tetrah. Let. 1972, 2203. 

Diels-Alder addition product, from 1-methylpyrrole and maleic anhydride 2 is a further example of this sort of reaction. 2-Methylpyrrole behaves similarly, but the initial product (10) from pyrrole is obtained in small yield because it reacts further (p. 88). Pyrroles such as 2-methyl-, 1,2-dimethyl-and 2,4-dimethyl-pyrrole undergo similar Michael additions with methyl acetylenedicarboxylate s, 254 jn the third instance two molecules of the pyrrole reacting to form (11). 1-Methoxycarbonylpyrrole reacts at the 2-position with acetylene dicarboxylic acid254 as well as giving a Diels-Alder type of product (p. 82). With the same acid, ethyl 3,5-dimethylpyrrole-2-carboxylate undergoes Michael addition at the vacant jS-position giving (12). Other examples of reactions with dienophiles are discussed below... 

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