Amidines from ammonia

Tetrakis(dimethylamino)titanium is a useful reagent for preparing amidines from secondary amides. From A X-thionyldiimidazole and secondary amides of boA aromatic and aliphatic carboxylic acids amidines (313 Scheme 50) are formed under mild conditions in moderate to good yields. N-Tosyl-amidines (314) can be obtained by reacting secondary thioamides (aliphatic and aromatic) with tosyl azide. Thiobenzamides have been condensed with anilines to afford amidines (315). Thioamides can be converted to amidines, e.g. (316), by treatment with ammonia in the presence of mercury acetate. ... 

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 ... 

The group at Merck, Inc. formylated ethyl 3-ethoxypropanoate at the a-carbon with ethyl formate in the presence of ethoxide and then treated the resulting aldehydic ester with the amidine from acetamide. The resulting 4-hydroxy-5-( 3-ethoxyethyl)-2-methylpyrimidine yielded the corresponding 4-chloroderivative with phosphorus oxychloride, which, with ethanohc ammonia produced the 4-amino-5-(P-ethoxyethyl)-2-methylpyrimidine. Ether cleavage to the P-bromohydrobromide produced the immediate precursor to the thiamine hydrobromide (Scheme 12.91). 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Diphenyl-l,2,4-thiadiazole results in small quantities, together with 2,4,6-triphenyltriazine and other products, from the action of alcoholic ammonia and mercuric oxide, or mercuriammonium chloride, or lead hydroxide on A-thiobenzoylbenzamidine (78 R = Ph),10B and from the treatment of the mercuric chloride-adduct of this substituted amidine (78 R = Ph) with potassium hydroxide104 (probably by air oxidation). 

N1 -Carboxamide-N-Guanyi Triazene [Triazendi-carbon saureamid-amidin (Ger)] H2N.CO.N N.NH.C( NH).NH2+H2 Of C2H8N602 mw 132.16 N 63.60% OB to C02 +24.21% yel ndles (from hot w) mp, decomps explosively at 95°, puffs off at 139° on rapid heating. V sol in alkalies si sol in w. Prepn is by gently warming N-aminoim inome thy 1- N-carb onic acid ethyl ester-triazene with ammonia. The compd forms expl salts such as the Hydrochloride, C2H6N60+HC1 mw 167.09 N 50.31% ... 

The initial synthetic approach to conivaptan HCl (1) employed by the Yamanouchi discovery group26 commenced with commercially available benzazepinone 10. Acylation of 10 with p-nitrobenzoyl chloride provided benzamide 11. Subsequent hydrogenation of 11 over palladium on carbon yielded aniline 12, which was in turn condensed with biphenyl-2-carbonyl chloride to provide bis(amide) 13. Bis(amide) 13 was subsequently heated with copper(II) bromide in boiling chloroform/ethyl acetate to furnish a-bromoketone 14. It is interesting that condensation of a-bromoketone 14 with acetamidine hydrochloride in the presence of potassium carbonate in boiling acetonitrile afforded not only the desired imidazobenzazepine product (1 53% yield, 2 steps) but also the related oxazolobenzazepine 15 (7% yield, 2 steps), which presumably resulted from nucleophilic attack of the benzazepinone oxygen on the amidine moiety followed by loss of ammonia. Separation of oxazolobenzazepine byproduct 15 from imidazobenzazepine 1 by silica gel chromatography followed by treatment of the purified imidazobenzazepine free-base with hydrochloric acid then provided conivaptan HCl (1). 

Evidence that aminonitriles and 2-aminoindoles are the intermediates in this cycli-zation leading to indoles was obtained with a-substituted 2-nitrophenylacetonitriles. The final absorption of 1 mol of hydrogen was slow in the hydrogenation of 42, ammonia was not formed, and the aminonitrile 43 was the product, which cyclized to the oxindole 44 in the presence of acid. The hydrogenation of P-dimethylaminoethyl-sub-stituted nitronitrile 45 over 10% Pd-C in ethyl acetate at 80°C afforded ammonia and the indole 46. However, the hydrogenation of 45 over 8% Pd-C in acetic acid at 80°C did not result in the formation of an appreciable amount of ammonia, and a crystalline dihydrochloride corresponding to an amidine structure 47 could be prepared from the product (Scheme 9.17). 

The reaction of amines and ketene acetals was used as a main synthetic approach to 1,1-enediamines in earlier years72. Both simple and conjugated 1,1-enediamines can be obtained by this route. Displacement reaction of ketene acetal 34 with two equivalents of piperidine furnishes 1,1-dipiperidinoethene (35) in 62% yield (equation 9)73. Primary amines and ammonia react with 34 to give amidine derivatives. Cyano-74 and trifluor-oacetyl-substituted enediamines75 have been synthesized from the corresponding ketene acetals in good to excellent yields (e.g. equation 10). 

Certain nitriles add amines to form N-substituted amidines. This reaction has been modified and extended through the use of ammonia and alkyl- or aryl-ammonium salts of sulfonic acids. Many amidines have been prepared in yields ranging from 13% to 86%. Some amidines are obtained in better yields by heating a cyanide with ammonium thiocyanate or an alkylammonium thiocyanate."... 

The inner amide group is activated and then converted into an amidine by the addition of ammonia derived from glutamine. 

Imidazoles can be made by 1,5-dipolar cyclization of suitable 2-azavinamidinium salts [6. 7]. Such salts (10) are readily made from amidines (or guanidines) and amido or ureido chlorides (9), and in the presence of sodamide in liquid ammonia they cyclize to form electron-rich imidazoles... 

There are standard methods available for synthesis of amidines 10] and guanidines. In particular, reaction of an acylated thiourea with an amine, followed by removal of the acyl group(s) from the acylguanidine intermediate provides a mild and efficient synthesis [11]. When dihydroxyacetonc is treated with formamidine acetate in liquid ammonia, imidazole-4-methanol is isolated in 65-70% yield as its hydrochloride (3) (Scheme 4.3.2). This convenient synthesis is much less tedious than the old approach based on the reaction of fructose with ammonia [16]. 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

The amidine-functionalized cobalt(III) sarcophaginates with apical carboxylic acid and the complex resulting from its decarboxylation, as well as the [Co(MEazasar)]3+ azasarcophaginate (formed by capping with ammonia resulting from the hydrolysis of the ethyl cyanoacetate nitrile groups), are minor clathrochelate products of this reaction [134]. 

Apart from the bases mentioned a series of other nitrogen bases (ammonia, triethylamine, pyridine, cyclic amidines, lithium diethylamide, lithium diisopropylamide, lithium piperidide, etc.) have been used to deprotonate phosphonium salts. 

The action of ammonia, primary and secondary amines on alkoxymethyleneiminium salts or alkylmercaptomethyleneiminium salts affords amidinium salts. Provided the educts are chosen in such a manner that the substitution pattern of the resulting amidinium salts does not exceed that of A/jV.AT -trisubstituted salts, the amidines can be released from the salts by addition of bases (see also Section 2.7.2.5.3). Very often the alkoxymethyleneiminium salts were prepared in situ and reacted without further purification with the amino compound to give the desired amidine. This amidine synthesis is of special synthetic interest, since it was stated that formamidines, derived from alicyclic amines, e.g. (306 equation 164), which are simple to obtain by this method, are readily transformed to reactive carbanions. Heterocycles, e.g. (307 equation 165), containing amidine structures, are accessible by reaction of appropriate difunctional compounds with iminium salts. ... 

As already mentioned the action of ammonia, primary and secondary amines on imidoyl halides affords amidinium salts, from which the amidines (3 Scheme 57) can be set free by treatment with bases (see Section 2.7.2.5.3 and 2.7.2.S.4). In imidates and thioimidates the al-koxy groups and alkylmercapto groups respectively are readily replaced by amino groups giving amidines (340). 

Applications in organic synthesis of the iminoacylation reaction of oximes have recently been found at kinetically labile Zn11- or Con-oxime systems. The former catalyzes the hydrolysis of nitriles to carboxamides (23)37 and the Co11 system catalyzes the conversion of nitriles into amidines (24) (also involving C N bond formation upon reaction with ammonia, formed from competitive hydrolysis of the nitrile).110... 

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. ... 

Three-membered rings with two heteroatoms are usually encountered only as reagents. Diazirines are nsefnl carbene precnrsors" - they are generally more stable than the equivalent isomeric diazo compounds, thongh they are sometimes explosive in the pure state. They can be prepared by oxidation of diaziridines that, in tnm, are available via the condensation of a ketone or aldehyde with ammonia and chloramine. Chloro-diazirines, from the reaction of amidines with hypochlorite, wiU undergo Sn2 or Sn2 displacement reactions."" ... 

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