Amidines from imidates

Scheme 3.11 Synthesis of cyclic amidines from imidate and aziridines...

Amidines 21 derived from imidates 20 and thiophenes 1 were cyclized into... 

Unsymmetrically substituted 1,3,5-triazines can be obtained by the reaction of amidines with imidates.316,482 484 Generally, the predominating product has one substituent derived from the amidine and two from the imidate reactant. 

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 ... 

K. Kaji, H. Matsubara, H. Nagashima, Y. Kikugawa, and S. Yamada. Synthesis of form-amidines from carbodi-imides with sodium borohydride in isopropanol. Ghent, and Pharm. Bull. Japan), 1978, 26, 2246. 

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. 

Table 18 Synthesis of 1,3,5-Triazines from the Reaction of Imidates and Amidines (62JOC3608)...

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. 

Unprecedented dihydrodipyridopyrazines were easily obtained by hetarynic dimerization of 2-alkylamino-3-halopyridines <02T3513>. The reaction of hexamethylphosphotriamide with amidines derived from Af-benzimidazoyl imidates 81 afforded benzimidazolo-1,3,5,2-triazaphosphorine 2-oxides 83 in good yield. When the condensation was carried out at room temperature /V-phosphonic amidines 82 could be isolated <02PS1033>. 

Azidoformomidine or Guanylazide (Triazo-fotmamidin, Carbamid-imid-azid or Kohlen-saure-amidin-azid, in Ger), N3C(=NH)NH2 mw 85.0 7, N 82.33%, OB -65.9%- Prepd from the nitrate salt (which was prepd from aminoguanidine nitrate and nitrous acid) by treatment with NaOEt in ale, but quickly rearranged to the Tetrazole. Consequently, it is known only as its salts Ref l) Beil 3, 130, (60) 2391... 

The general approach of amidine cyclization ha.s been applied to the synthesis of a variety of 2-substitutcd imidazoles. Aminoacetaldehyde dimethyl and diethyl acetals are readily available commercially, and the N-subsiituted derivatives can be made with little difficulty, providing access to 1-substituted imidazoles on reaction with a suitable imidate. Thus, methyl -hydroxypropanimidate (2), prepared from 3-hydroxypropanenitrilc, and methanolic HCl, condenses with an aminoacetaldehyde acetal to give the amidine hydrochloride (3), which ring closes when heated in acidic medium to form the 1-substituted 2-hydroxyethylimidazolc (4) (Scheme 2.2.3) [6J. The reaction has been adapted to the preparation of 2-arylimidazoles [5, 7-11],... 

The aldehyde (5) can be made in high yield from the amidine (6) via the unisolated 2-dichloromethylimidazole (Scheme 2.2.3). Dichloroacetonitrile is converted into its imidate with methanolic sodium methoxide, and then into the amidine with aminoacetaldehyde dimcthylacetal. When (6) is heated in formic acid it is converted almost quantitatively into the 2-carbaldehyde the use of trifluoroacctic acid at reflux gives around 60% of (5). Using essentially the same method, imidazole-2-carboxylic acid and its ethyl ester can also be made veiy efficiently when trichloroacctonitrilc and the acetal arc used to prepare the amidine [16],... 

Amidines of aliphatic acids are generally not reducible in buffered solution. Some amidines derived from aromatic acids are reducible at very negative potentials and only in a narrow pH interval from slightly acid to alkaline solution. The reduction is similar to that of imidic esters [Eq. (10)], and yields the amine [44]. 

Metal amides can be added to ordinary nitriles e.g. lithium, sodium or magnesium amides), thus forming amide imide salts, which on addition of water or alcohol afford amidines. Some recent results demonstrate the wide applicability of the method, e.g. from metal amides and trialkoxyacetonitriles, tri-alkoxyacetamidines (319 Scheme 52) were prepared and from lithium imides and nitriles A -alkylide-neamidines (320) could be synthesized. 

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). 

Imidates react with thiophenes 30 analogously. In the reactions of N-substituted imidates, the initially formed thienopyrimidineimines 50 undergo cyclization to give aminothienopyrimidines 51 (1986CB1070). Amidines 101 can also be prepared from... 

Since the discovery of the synthesis of 1,3,5-triazine-2,4-diamines from biguanide and its derivatives,328-329 a large variety of carboxylic acid derivatives, e.g. acid chlorides,332 342,346 lactones,333 amides,334,335 imides,336,337 ortho esters,338 amidines,338 esters334, 339- 343 and acid anhydrides,332,344,345 have been used as starting materials in the preparation of these triazines (Table 8).330,331 The preferred procedure is the reaction of biguanides 1 with esters 2 in alcoholic solution, sometimes in the presence of a basic catalyst. The reaction mechanism is thought to be as indicated.341... 

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