Benzamidine, reaction with

Mefenidil (78) is a cerebral vasodilator which may be of value in treating geriatric cerebral circulatory problems. It can be synthesized by reacting benzamidine (76) with biacetyl to produce the highly reactive methylene benzimidazole adduct 77. Reaction of the latter with sodium cyanide completes the synthesis 1,26]. 

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

When the reaction of diethyl oxomalonate 381 was carried out with the free 5-methyl isothiosemicarbazide, triazine 281 was obtained in addition to its isomeric triazine 382. Reaction of 382 with phosphorus oxychloride gave 383, whose reaction with guanidine or benzamidine gave 384, which cyclized to 385. This represents (85JOC2293) the first example of a preparation of this bicyclic system from a 1,2,4-triazine. 

The challenging question can be raised as to whether the formation of 109 can be explained in an alternative way, i.e., by a Diels-Alder reaction with an inverse electron demand, in which the C = N group of the electron-rich benzamidine forms a regiospecific cycloadduct across the 1,4-position... 

The pyrimido[4,5- ][l,2,4]triazines (6-azapteridines) 18a and 18b, shown in Scheme 18, were formed upon the reaction of the ethyl l,2,4-triazine-6-carboxylates 121 with benzamidine, a reaction which proceeds via the action of boiling acetic acid upon the characterized intermediate salt 122 <2003CCC965>. The same researchers (Scheme 19) also showed that the 5-amino-l,2,4-triazine-6-carboxamide 123 (R =OMe) can undergo reaction in neat benzaldehyde to furnish a low yield of the 6-azapteridine 18b. More importantly, the 5-amino-l,2,4-triazine-6-carboxamides 123 were found to undergo reaction with triethyl orthoformate to yield the 6-unsubstituted-3-arylpyr-imido[4,5-( ][l,2,4]triazines 18c and 18d, also shown in Scheme 19 (R = H) <2003CCC965>, one of only a few entries to such compounds. 

A few cases of [4 + 2] cycloaddition reactions of 1,2,4-triazines with C=N double bonds have been reported. Reaction of 1,2,4-triazines (441) with benzamidine (442) in boiling toluene led to the isolation of the 1,3,5-triazines (443). It may be supposed that here the dienophile adds to the 2- and 5-positions of the 1,2,4-triazine, as in the reaction with ynamines, then a nitrile (R6CN) is eliminated and aromatization follows by loss of ammonia. In one case, the initially formed 1,3,5-triazine (443) reacted with a second molecule of benzamidine by [4 + 2] cycloaddition and elimination of R3CN and ammonia, resulting finally in triphenyl-1,3,5-triazine (444). This is a known reaction in the 1,3,5-triazine series (see Chapter 2.20) (81TL1393). 

Bacteriochlorins, 851 Barbituric acid metal complexes, 798 Barium alkoxides synthesis, 336 Barium complexes phthalocyanines, 863 porphyrins, 820 Becium homblei copper accumulation, 964 Benzaldehyde, 2-amino-self-condensation aza macrocycles from, 900 Benzamide, o-mercapto-metal complexes, 655 Benzamide oximes metal complexes, 274 Benzamidine, /V, V -diphenyl-metal complexes. 275 Benzene, 1,2-diamino-reactions with dicarbonyl compounds aza macrocycles from, 902 Benzene, 4 methylthionitroso-metal complexes, 804 Benzenedithiolates metal complexes, 605... 

Amidines and thioamidines can also be viewed as urea-like binucleophilic compounds. There are a series of publications about their treatment with unsaturated carbonyls [7, 86, 87, 88, 89, 90, 91, 92]. The most general reaction products in this case are 1,4-dihydropyrimidines or 1,6-dihydropyr-imidines. Interaction of acetamidine 88 with mesityl oxide 52 [86] and benzamidine 90 with arylidenetetraline 91 [91] led to the corresponding 1,6-dihydropyrimidines 89 and 92, while the reaction of bezamidine and benzylideneacetone 24 yielded 1,4-dihydropyrimidine 93 [87] (Scheme 3.27). 

Formamidine reacts with a-hydroxyketones95 and a-haloketones62 to yield oxazoles and imidazoles. Normally the formamidine is liberated from its hydrochloride by the addition of sodium butoxide in n-butanol. It is interesting to note that in the reaction with a-hydroxyketones, the aliphatic acyloins yielded mainly imidazoles (35-68% yield), whereas the benzoins gave mainly oxazoles (67-80%).95 Unlike formamidine, acetamidine and benzamidine react with both aliphatic acyloins and with benzoins to yield imidazoles exclusively.65 Bredereck65 explains the reactions as follows ... 

Unlike formamidine, acetamidine and benzamidine react with both aromatic and aliphatic a-hydroxyketones to give imidazoles exclusively. It has been suggested that aryl groups favour the enolic form (2) of the tautomeric mixture, resulting in the formation of oxazoles as major products. Aliphatic groups favour the keto form (1), from which imidazoles are derived. That amidines more complex than formamidine favour imidazole formation may be a consequence of steric hindrance to reaction of the enolic hydroxy groups with the amidine carbon in (2). The general reaction has been used to prepare such compounds as 4,5-dipropyl imidazole (25% yield from tris(formylamino)-methane and 5-hydroxyoctan-4-one), and a variety of 2-imidazolones and 2-aminoimidazoles [8]. The fact that oxazoles can be converted into imidazoles with some ease extends the applicability of this reaction. 

The reaction sequence of Scheme 3 might well be classified as an imidazole synthesis from other heterocycles, but it seems more logical to treat this as a cyclization involving formation of the 1,5-bond. The enaminoketone condensation products (12) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds are cyclized by base to imidazoles (13) in 60-80% yields." Such a reaction makes use of the well-established general attack of a nucleophilic center in the side chain on N-2 of the oxadiazole ring. Benzamidine combines with 2-amino-3-phenacyl-l,3,4-oxadiazolium bromides to produce 1-acyl-amino-2-benzimidoylamino-4-arylimidazoles. ... 

Amidinate ligands. The benzamidinate ligand has also been found to coordinate the uranyl ion. The uranyl complex, [CgH5C(NSiMe3)2]2U02, was prepared by a metathesis reaction with UO2CI2. ... 

The acetates of acetamidine and benzamidine were condensed with 4-aminotriazole-S-carboxamide (73a) and its 7- and 8-methyl derivatives to give 2-metoyl- and 2-phenyl-8-azapurin-6-ones, respectively, in 80-90% yield, after refluxing for 4 - 8 h in butanol, hexanol, or octanol (toe choice of solvent determined toe optimal yield in each case). The reaction with tri-chlOFoacetamidine terminated at, e.g., (a-amino-i ) )9-trichloroethyliden-amino) 1,2,3-triazole (84) (from 73a). These intermediates were cyclized to 2-trichlorometoyl-8-azapurin-6-ones, in excellent yields, by stirring with 0.5 N potassium hydroxide (24°C, 5 h). This reaction gave only poor yields with 73b,c. 

The crystal structure demonstrates that the Sn lone pair of electrons is stereochemically active. The analogous reaction with a benzamidinate gives a higher yield of product... 

Analogous condensation with guanidine gave 2-aminopyrimidines (e.g. 28 a) reaction with benzamidine gave 2-phenylpyrimidines (e.g. 28b). 

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