Ketones from amidines

In conclusion, a scaleable process for the preparation of 2,4-subsituted imidazole from amidines and a-halo ketones is described. This method avoids the use of chloroform as solvent and affords the desired products in consistently good to excellent yields. 

Synthesis from amidines, isocyanates, aldehydes and ketones 512... 

Imidazoles 4, with a variable substitution pattern, are obtained from cr-halo or a-hydroxy ketones and amidines ... 

Reaction of carbanions with TNB may result in the formation of new carbon-carbon bonds. Examples of adducts formed are (63) from ketones [166], (64) from aliphatic nitro compounds [167], and (65) from malononitrile [168]. ThCTe are various possibilities for furtho- reaction of these adducts. These include the formation of diadducts or of uicia-bridged adducts, such as (66), from suitable ketones [169,170] or from amidines, or of the ionization of the exocyclic hydrogen in (65) to give a dianion. 

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). 

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

Amidines 9 with an appropriate ortho-carbonyl substituent, which are obtained from the respective ortho-carbonyl aniline derivatives and 0-ethyl succinimide (5-ethoxy-4,5-dihydro-3//-pyrrol-2-one), are cyclized with sodium in alcohol to quinazolin-4(3// )-ones 10a and quinazolines 10b with a 2-[(alkoxycarbonyl)ethyl] substituent at C2. The reaction can also be carried out starting from anthranilates or 2-aminophenyl ketones as a simple one-pot synthesis. ... 

The reaction between a suitable imidatc and an a-aminoaldehyde or a-aminoacetal to form an amidine, which cyclizes to an imidazole, rests largely on the availability of the aminoaldehydes from a-amino acids, which are readily reduced using the Akabori method [2], Dimethyl or diethyl acetals frequently replace the aldehydes in these reactions 13,4]. Table 2.2.1 lists some 2,5-disub.stituted imidazoles prepared (ultimately) from amino acids. It is not possible to introduce a range of substituents at both the 4- and 5-positions by this method unless the amino acid is converted into a ketone rather than an aldehyde (see Section 2.1.1) (Scheme 2.2.2). 

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