Amidines from orthoesters

Acylation of nitrogen compounds by orthoesters. The formation of amidines from orthoesters (preferably orthoformates) and ammonia or an aromatic amine has been known for about 100 years (for a review see Post803). As an example for the acylation of ammonia a modern procedure is reproduced, in which acetamidine is obtained as acetate 804... 

Acylation of nitrogen compounds by imidic esters. It was mentioned above that synthesis of amidines from orthoesters proceeds through imidic esters, so that both classes of compound are normally treated together in reviews.819-821 Accordingly, also, it is, of course, possible to use imidic ester hydrochlorides as usually prepared from nitriles and to treat these with ammonia or amines.820 Care must be taken, however, with primary amines lest the imido group be also exchanged for the residue from the amine, particularly at higher temperatures ... 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitnles arises both from the reactivity of the C=N bond, and from the abiHty of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxyHc acids and esters, aldehydes, ketones, large-ring cycHc ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy pubHshed (10). 

Abb. 7.14. Imidic acid ester hydrochlorides (F)—to be prepared from nitriles, hydrogen chloride (gas) and methanol acc. to Fig. 7.13—, their trans-formability into orthoester (A) or amidine (I) and the corresponding reaction mechanisms. 

The dinitriles for the preparations of (320) to (323), were best obtained from the appropriate dibromoalkane and the sodium 4-cyanophenate. In the subsequent Pinner reaction it was found that an excess of ethanol was needed to get good yields of the ethyl imidate salt and a large excess of alcoholic ammonia ensured efficient conversion to the amidine since the imidate base reacts preferably with ammonia, but any traces of the salt tend to react with solvent to give the triethyl orthoester [39(U392], 4-Bromophenol reacted with K CN in the presence of copper(II) sulphate and sodium bicarbonate to give radioactive 4-hydroxybenzonitrile which was converted by the above procedure to pentamidine labelled at the... 

Orthoesters react with excess amines, catalyzed by acids, to afford amidines imino esters are isolable intermediates (see Section 2J.3.2.3). A lot of Af-m diylformaniidines, Af-pyridylfotmamid-ines and iV, -diphenylfomiainidiiies (354 Scheme 60) were prqtared by this method. In a similar reactitm from dichlorofluottHnethane and pentafluotofnmanilide formamidine (355) was prepared. The condensation of NH-acidic compounds with orthoamide derivatives affords amidines (356) and (357) (Scheme 61). This is one of the most general and easy to perform syntheses of amidines, which has found wide application in the last 15 years. In Tables 7a and 7b are compiled orthoamide derivatives and amino compounds which have been reacted to give amidines. 

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