Igor I. Boiko, Tatyana N. Boiko

Technologist Co., Ltd. Mendeleev sq. 2, Pereslavl-Zalesskiy, Yaroslavl reg., 152125, Russian Federation. E-mail: technolog@slavich.ru

Pyrrole deivatives are used as synthones for biologically active compounds synthesis [1]. Therefore every new type of substitution in pyrrole ring and improvement of pyrroles synthesis are in konstant interest.

Moreover, due to relative low molecular weight, pyrrole derivatives substituted with reactive groups serves as building-blocs for synthesis of pharmacologically active compounds. Such building-blocks synthesis is one of kinds Technologist Co., Ltd. activities.

We have elaborated a convenient way for obtaining of 3-alkoxycarbonyl-5-aryl-2-methylpyrroles with or without substituents at nitrogen atom (Scheme 1).

Scheme 1

2a: R=R'=H, 96,5%; 2b: R=4-CH₃, R'=H, 80,3%; 2c: R=4-CH₃O, R'=H, 94,9%; 2d: R=H, R'=CH₃, 85%; 2e: R=4-F, R'=H, 85,6%; 2f: R=4-CH₃O, R'=CH₃, 60%; 2g: R=4-iC₃H₇O, R'=H, 48,6%.

Correspondent phenacylbromides (2) were synthesised as described in [2] by bromination of acetophenones and propiophenones (1) (1-2 moles) with bromine in ethanol. As we have mentioned, the yield decrised when water content in alcohol incrised. Moreover, acetophenone alkoxy derivatives partly dealkoxylated in reaction condition leading to decrise yield and purity of desired product 2. At Scheme 1 optimised yields of α-bromoarylketones 2a-g are showed.

α-Bromoarylketones 2a-g thus synthesised were subjected to reaction with sodium ethyl acetoacetate obtained in situ, in corresponding absolute alcohol as described in [3] or ethyl ether as described in [4]. As result syntheses of phenacylacetoacetic acid esters (3) were synthesised in high yields (85-100%). Majority of esters 3 appears as viscous oils which during attempt of their distillation in vacuo (3-5 mm Hg) vigorously decomposes at the bath temperature over 160˚C. Therefore crude phenacylacetoacetic acid esters 3 isolated from reaction mixture by treating with water and ethyl ether extraction after removing of solvent in vacuo without further purification were condensed with primary amines. Condensation reaction was carried out in alcohol saturated with hydrogen chloride or in acetic acid. After dilution of reaction mixture with water crude product was filtered or extracted with ethyl ether and solvent removed. Crude compounds 4 thus isolated were recrystallised from alcohol (except of oily products).

3-Alkoxycarbonyl-5-aryl-2-methylpyrroles (4) thus obtained are listed in Table 1. Purity of compounds obtained was confirmed by TLC.

Table 1.

* crude product

Hydrolysis of pyrrole 4 alkoxycarbonyl group at several hours reflux in excess of alcoholic solution of potassium hydroxide proceeds with high yields, sometimes quantitative (Scheme 2).

Scheme 2.

Obtained substituted 3-pyrrolecarbonic acids (5) can to be used for synthesis of plurality their derivatives. Their properties showed in Table 2.

Table 2.

Unsubsituted 3-position of pyrroles 4 gives a possibility for functionalisation, for instance with acetyl or formyl group. We have done the latter transformation by Wilsmayer-Haack formylation of 3-ethoxycarbonyl-2-methyl-5-phenylpyrrole (Scheme 3).

 Scheme 3.

The aldehyde 6 was obtained in 70% yield, m. p. 160˚C.

Thus, as result of our investigations, we have elaborated convenient preparative method for obtaining 3-pyrrolecarbonic acids and their esters on examle of more than 50 compounds.

References

1. J. S. Aggarwal, A. U. Qugeshi, J. N. Ray. Chemotherapy: attempts to find antimalarials. II. Pyrrylindoles. J. Am. Chem. Soc., 1932, 54, 3988-3992.

2. Methods for chemical substances and preparates obtaining. Vol. 22. Moscow, IREA, 1970, 40-41. (Russian).

3. C. Paal. Ueber die Einwirkung von Bromacetophenon auf Natiumacetessigather. Ber. Deutshch. Chem. Ges. 1883, 16, 2865-2869.

4. I. Ossipoff, G. Korschun. Synthese des 2,5-Dimethylpyrrol-3-monocarbonsaureathylesters. Journ. Russ. Phys.-chem. Ges. (Tl. Chem.) 1903, 35, 630-635. (Russian). (Chem. Zentralblatt 1903, II, 1281).