Amidines from nitriles

Scheme 5. Preparation of silylated amidines from nitriles and subsequent reaction with (NSC1)3, SC12, SjNjCIj, etc.

Via intermediates Amidines from nitriles via carboxylic acid thioamides and thioiminoester salts... 

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. 

Removing the piece with the two heteroatoms from (43) leaves acetoacetate as one starting material the other is an amidine, easily made from nitrile (45). 

Triazoles have also been obtained when the carbon atom adjacent to the activated methylene group carries a nitrogen function (i.e., amides, nitriles, amidines, and imines - ). In many of these cases it is impossible to decide, without N-labeling experiments, whether the third nitrogen of the triazole ring is derived from the toluene-p-sulfonyl azide or from the activated methylene compound. With amides, amidines, and nitriles, the first possibility seems more reasonable, but with imines, the third nitrogen is that of the imino group (Scheme... 

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 appropriate amidines can be made from nitriles and metal amides, but reaction conditions appear to be critical with best yields reported using DMSO-THF. Alkylchloroaluminium amides, which can be generated from trimethylaluminium and ammonium chloride or amine hydrochlorides, have been shown to add efficiently to nitriles to give high yields (60-95%) of suitable amidines. Similarly, (V-alkylcyanamides can be converted into guanidines, in an approach which appears to be useful and potentially quite general. Yields, however, arc not always good [56],... 

Methods derived from this fundamental process involve the condensation of one-, two- and three-carbon units such as amidines, amino-nitriles and carboxamides, which represent intermediate stages of the ammonia/hydrogen cyanide reaction. Pyrimidines or imidazoles are usually intermediates. ... 

Synthesis of imino ethers, amidines and orto esters from nitriles (see 1st edition)... 

Imidoyl amidines 1 can be synthesized starting from amidines and nitriles. Subsequent cycliza-tion with carboxylic acid anhydrides provides the corresponding 1,3,5-triazines 2. 

The usual procedure36 is to add a slight excess of a secondary amine to an ethereal solution of ethylmagnesium bromide (50% excess relative to the nitrile) and, when evolution of ethane ceases, to heat the mixture under reflux for about 20 min before adding an ethereal solution of the nitrile the whole is then boiled under reflux for 2-3 h, then decomposed with ice. In many cases this method is superior to the Pinner synthesis of amidines from imidoyl esters. 

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 ... 

Thioimidic esters. These esters are convenient precursors of amidines and they are prepared from nitriles and PhSH in the presence of HBr. 

Amidines from amines and nitriles. CuCl activates ordinary nitriles towards attack by amines except those with low nucleophilicity (e.g., ArNH2). 

Amidoximes [RC(NH2)=NOH], which are obtained from nitriles on reaction with hydroxylamine, are hydrogenolyzed (Hj, Pd/C, HOAc-AcjO) to give amidines. ... 

Imidates derived from nitriles and alcohols are also effective precursors for the preparation of amidines. For example, furamidine, known as an active compound towards parasitic microorganisms and DNA minor groove binder [22], and its derivative DB-181, were synthesized from nitrile via the corresponding imidate [23] (Scheme 3.9). 

Synthesis of Amidines from Amines and Nitriles. An efficient one-step preparation of Af,Af -disubstituted amidines is possible by direct nucleophilic addition of an amine to a nitrile using catalytic amounts of samarium iodide (eq Alternatively, an... 

Continued interest (Vol. 1, p. 259) has been shown in the preparation of sy/M-triazines bearing fluorinated substituents. A review of perfluoroalkylene-triazine elastomers has been published two separate approaches (Scheme 59), the acylation-cyclodehydration of imidoylamidines, formed from amidines and nitriles, and the free-radical coupling of preformed triazine derivatives, have been used successfully to produce polymers of good linearity. 

Lithium n-propylmercaptide in hexamethylphosphoramide provides a mild system for the rapid dealkylation of quaternary ammonium salts, with high propensity for methyl group removaL. Substituted amidines have been prepared under very mild conditions from nitriles, halides, and amines with the help of a Lewis acid such as ferric chloride . a,a-Dichloro-/ -ketoesters undergo a rapid fragmentation with nucleophiles, even with relatively weak ones such as diethylamine, and can thus serve as acylating agents... 

Carboxylic acid tbioamides from amidines and nitriles Perfluorothioamides s. 13, 604 CSNH2... 

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 other main reaction in this class is the Dieckmann-type cyclization of the intermediates (163) from 4(6)-halo-5-ethoxycarbonylpyrimidines with AC-substituted /3-alanine esters and nitriles, and related compounds, to give 5,6,7,8-tetrahydro-5-oxopyrido[2,3-[Pg.221]

Among other bicyclic amidine catalysts, 3,4,6,7,8,9-hexahydro-2//-pyrido[l,2-n]pyrimidine was also applied in the preparation of /3-alkoxy nitriles from Q ,/3-unsaturated nitriles and alcohols (99GEP 19803515). The azido group could be smoothly converted into a trifluoroacetylamido group by treatment with (Cp3CO)2 in the presence of Ph3P and 2,3-dihydro-2//-pyrido[l,2-n]pyrimidin-2-one under Ar in THE (99HCA2380). 

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