Opening of the extra ring in pheophorbide a methyl ester by the action of amines differing in the number, size, and structure of substituents on the nitrogen atom was studied with a view to synthesize chlorine e 6 13-carboxamides. Main factors restricting one-step preparation of 13-carboxamides with a desired substituent were revealed. The obtained experimental data can be used as a basis for predicting the possibility for onestep preparative synthesis of particular chlorin e 6 13-carboxamide via reaction with one or another amine.Natural chlorins are known as starting compounds for the synthesis of biologically active substances, such as diagnostic and antitumor agents for oncology, wound healing preparations, etc. [1][2][3][4][5][6][7]. Development of efficient procedures for the introduction of additional substituents at the periphery of chlorin macroring attracts strong interest from the viewpoint of analysis of structure-biological activity relationships and synthesis of new biologically active compounds. In the preparation of medical agents, of particular importance are experimentally simple reactions leading to formation of large series of structurally related compounds. The above requirements could be met by opening of the extra ring in pheophorbide a methyl ester (I) by the action of amines. These reactions could give rise to the corresponding chlorin e 6 13-carboxamides (Schemes 1, 2) [8][9][10][11][12][13][14][15][16][17][18]. The products of such transformations contain various fragments attached to the nitrogen atom at the periphery of the chlorin macroring; therefore, opening of the extra ring in pheophorbide a methyl ester (I) by the action of amines is successfully used to synthesize in one step chlorine e 6 13-carboxamides having various substituents at the periphery.The available published data do not allow us to denote the scope of application of the above reaction in the preparative chemistry of chlorophylls and their derivatives. Amines used previously had fairly simple structure and spatially accessible nitrogen atom linked to aliphatic substituents, so that the effect of substituent on the nitrogen atom could not be estimated. Cleavage of the extra ring in I by the action of amines was reported to occur only at room temperature (reaction time 1-48 h) in chloroform, methylene chloride, or THF; therefore, we were unable to reveal the effect of reaction condition on the basis of published data. From the mechanistic viewpoint, opening of the extra ring in pheophorbide a methyl ester (I) and its analogs by the action of amines is nucleophilic substitution at the carbonyl carbon atom in position 13 1 (Scheme 2). This process, like all analogous reactions of carbonyl compounds, is influenced by the partial negative charge on the unshared electron pair on the nitrogen atom, as well as by the size, structure, and number of substituents thereon, which determine spatial accessibility of the unshared electron pair and formation of tetrahedral (sp 3 ) intermediate [16]. Published data on the reaction me...
Alkylation of phenol by myrtenol in the presence of aluminum phenoxide and aluminum isopropoxide was studied in the temperature range 120-160°C. The reaction occurred with the formation of an array of alkylated phenols. Isomerization of the terpene substituent as a result of rearrangements of the bicyclic myrtenol structure was observed. The side reaction of myrtenol reduction occurred during the alkylation in the presence of aluminum isopropoxide. A significant number of compounds with two aromatic moieties was formed in the presence of aluminum phenoxide.Terpenophenols are known to exhibit a variety of biological activities [1][2][3]. The presence of isoprenyl substituents modifies the role of the aromatic compounds, mainly by increasing their lipophilicity. This enhances the retention of the prenylphenols in lipid cell membranes and the penetration through them [4]. The structure of the terpene substituent and the terpenophenol in general can determine the type of activity. In this respect, studies elucidating the relationship between the alkylation conditions and the resulting products are interesting. The goal of such investigations is to find the parameters that facilitate the selective production of compounds with a given structure.Herein the influence of two organoaluminum catalysts, aluminum phenoxide and aluminum isopropoxide, on the products formed by alkylation of phenol (1) with myrtenol (2) (Scheme 1) is evaluated taking into account various thermal regimes and reagent ratios. According to the literature [5][6][7][8], both catalysts are ortho-orienting.Phenol, aluminum phenoxide, and aluminum diisopropoxide-phenoxide were alkylated by myrtenol at 120, 140, and 160°C. The catalysts were aluminum phenoxide (PhO) 3 Al and aluminum isopropoxide (i-PrO) 3 Al. (PhO) 3 Al was produced in situ by reacting phenol with metallic Al. (i-PrO) 3 Al was transformed during the reaction into the mixed aluminum alkoxidephenoxide by reaction of equimolar amounts of phenol and (i-PrO) 3 Al.The alkylation with an equimolar ratio of aluminum alkoxides and myrtenol was carried out for 3 h with practically complete conversion of myrtenol regardless of the nature of the organoaluminum component. The reaction with a catalytic amount of the aluminum alkoxides occurred at temperatures of at least 160°C and continued for 8-15 h. The conversion of myrtenol was 50-60%. The reaction products were a mixture of O-and C-alkylated phenols and myrtenol derivatives (numbering of C atoms is given for convenience of reading spectra). These were monoalkylated phenols (3, 4); cyclic ethers (5, 8); a linear ether (9); substituted phenols (10-16); dialkylated phenols 17 (chromone and o-substituted), 18 and 19 (ortho and o-substituted), 20 and 21 (ortho-and para-substituted); ortho-disubstituted phenol (22); myrtenol derivatives (22-27); and myrtenol derivatives with two aromatic cores (28-33) (Scheme 1).A variety of structures for the terpene substituent was noted in the alkylation products. The presence of a strained cyclobutane moiety in th...
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