Benzimidazoles from Aldonic Acids

An intermediate diamide of the type XI, namely, di(D-gluco-D-(ofo-octonyl)-o-phenylenediamine, has been described by Hann, Merrill and Hudson.18 Under the normal conditions recommended by Haskins and Hudson,15 the crystalline product in this experiment was a mixture whose fractionation provided a 40% yield of the diamide and a 39% yield of the 

The procedure of Moore and Link16 is now generally preferred for the preparation of benzimidazoles from aldonic acids, their lactones, or their salts. Their specific example starting with calcium D-gluconate is given below. 

In the condensation from potassium salts, Moore and Link16 recommended that sirupy phosphoric acid (sp. gr. 1.7) be added, in amount equal to one-half the volume of concentrated hydrochloric acid that is used. While this may be of some advantage with acids, lactones, or salts of alkali metals, it tends to complicate the procedure starting with alkaline earth and other salts which will form insoluble precipitates when the reaction mixture is made basic with ammonium hydroxide. In such cases it is desirable to remove the interfering cation first. From the final alkaline solution even ammonium phosphate may crystallize during the process of concentrating a solution containing one of the more soluble benzimidazoles. 

The condensation of fatty acids with o-phenylenediamine has been carried out effectively by refluxing the components in 4 N hydrochloric acid.19 Moore and Link, in their second paper on the preparation of benzimidazoles,20 stated that this procedure gave less satisfactory yields with the aldonic acids, the yield from D-galactonic acid being only 24%. 

A word of caution at this point seems most desirable. In every case where a pure aldonic acid or its derivative has been heated with o-phenyl-enediamine and an excess of hydrochloric acid, only a single benzimidazole has been isolated. It is well known that aldonic acids are epimerized by heating them at temperatures above 100° with organic bases such as pyridine. The heating of an aldonic acid with o-phenylenediamine at 135-150° may also result in appreciable epimerization. Thus, Moore and Link20 reported that from the fusion of xylonic acid with o-phenylenediamine at 150°, in the absence of mineral acids, they could isolate the epimeric lyxo-benzimidazole. Barker, Farrar, and Gulland,21 in a more detailed study, proved conclusively that both D-ribo- and D-arabo-benzimidazoles were formed when the condensation of calcium D-ribonate with o-phenylenediamine was carried out in the presence of less than two molecular equivalents of hydrochloric acid, whereas with an excess of hydrochloric acid only the D-ribo-benzimidazole was obtained. It is important, therefore, in the condensation of o-phenylenediamine with an optically active acid at an elevated temperature that the reaction mixture always be kept on the acid side. 

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The melting points of the various benzimidazoles (see Table I) cover a considerable range of temperatures, and with the specific rotations as observed in N hydrochloric acid or 5 % aqueous citric acid (see Table I) will serve to characterize new and identify known benzimidazoles from aldonic acids. While the substances usually melt with decomposition, the values are readily reproducible. The rotations will be discussed further in the final section of this review. 

Ribose may be identified through the benzimidazole from ribonic acid, 2-(D-n6o-tetrahydroxybutyl)benzimidazole52 53 54 and its picrate and hydrochloride. However, caution must be used at two points in this procedure. In the first place, the customary oxidation of ribose with alkaline hypoiodite produces both ribonic and arabonic acids, the latter being formed by the alkali-induced epimerization of the former. While this epimerization may be avoided by using a buffered oxidizing mixture such as bromine-barium benzoate,65 there is, in the second place, further risk of epimerization during the condensation of the aldonic acid with o-phenylenediamine, particularly if there is insufficient acid present.9 10-11... 

The 2-(oMo-polyhydroxyalkyl) benzimidazoles are weak bases derived from o-phenylenediamine by condensation with an aldonic or closely related hydroxy acid. The present review includes substances of this type containing hydroxylated side chains of one to seven carbon atoms in length. Typical is the benzimidazole from D-glucose via D-gluconic acid. The side chain is attached at position 2 of the benzimidazole nucleus,... 

Crystalline benzimidazoles have been obtained from all aldonic acids so far tested with only one exception that is known to the writer. Lohmar and Link29 reported that the condensation of D-glucosaminic acid (= 2-amino-2-desoxy-D-gIuconic acid) with o-phenylenediamine under a variety of conditions failed to yield a crystalline product. The direct oxidative condensation of D-glucosamine hydrochloride with o-phenylenediamine in the presence of cupric acetate yielded only the known 2-(D-arofro-tetrahydroxybutyl)quinoxaline (III) and not the desired benzimidazole. 

The sugar benzimidazoles (VII), obtained from the condensation of aldonic acids with o-phenylenediamine, also readily undergo acid-catalyzed... 

The benzimidazole derivatives prepared from the aldonic acids have been suggested for the identification of sugars and acids (SO), The benzimidazoles are made by oxidation of the sugars to the aldonic acids, and subsequent condensation of the aldonic acids with o-phenylenediamine. 

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