Amidine formamidine acetate

The halonitro compounds and the methanol used were of purum or pract. quality from Fluka. The amidine derivatives (in the form of their salts) were purchased from Fluka or Aldrich (purum or pract.). The N,N-dialkyl-formamidine acetates were prepared by analogy to a published procedure (ref. 8) from cyanamide and used as isolated (containing ca. 10% ammonium acetate). 

Amidine derivatives are effective dehalogenation inhibitors for the chemoselective hydrogenation of aromatic halonitro compounds with Raney nickel catalysts. The best modifiers are unsubstituted or N-alkyl substituted formamidine acetates and dicyandiamide which are able to prevent dehalogenation even of very sensitive substrates. Our results indicate that the dehalogenation occurs after the nitro group has been completely reduced i.e. as a consecutive reaction from the halogenated aniline. A possible explanation for these observations is the competitive adsorption between haloaniline, nitro compound, reaction intermediates and/or modifier. The measurement of the catalyst potential can be used to determine the endpoint of the desired nitro reduction very accurately. 

Baumeister et al. studied the hydrogenation of various halonitrobenzenes using Raney Ni modified with amidine derivatives.115 Formamidine acetate (19b) has been found to be the most effective inhibitor for dehalogenation. It has been shown that the dehalogenation occurs as a consecutive reaction after the halogenated aniline has been formed. A typical example with use of this inhibitor is shown in eq. 9.51 for the hydrogenation of l-chloro-2,4-dinitrobenzene in comparison with dicyandiamide. It is noted that the reaction time could be shortened with 19b compared to that with 19a. 

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]. 

With some relief, it was found that replacement of orthoesters by amidines provided a reaction much less sensitive to conditions. Accordingly, the aminomethyl triazoles (96, and its 2-methyl and 3-benzyl analogs), as free bases, were refluxed in butanol with the acetates of formamidine, acetami-dine, and trichloroacetamidine (1 - 4 h), to give 60-95% yields of the corresponding l,6-dihydro-8-azapurines, which carried the characteristic group of the amidine in the 2 position. Thus 96 and trichloroacetamidine produced 7-methyl-2-trichloromethyl-l,6-dihydro-8-azapurine. With less avidity, a secondary amine, 4-amino-3-benzyl-5-methylaminomethyl-1,2,3-triazole, reacted with formamidine acetate in boiling butanol to give 9-benzyl-1,6-di-hydro-l-methyl-8-azapurine, and the best yield of 80% could be reached only when a new portion of formamidine acetate was introduced at 2-hourly intervals. ... 

Steric hindrance was encountered in applying this reaction to the synthesis of 1- and 3-methyl-8-azapurines. Thus, 4-amino-3-benzyl-5-methylamino-methyl-l,2,3-triazole reacted so slowly with formamidine acetate in boiling butanol that the amidine underwent destruction this situation was remedied by feeding in new supplies of the amidine every 2 hr, giving an excellent yield of 9-benzyl-l,6-dihydro-l-methyl-8-azapurine.63... 

Amidines have not found wide application for o-DAP cyclization apparently because they have no special advantages over other more accessible reagents. Mizuno et al. described the cyclization of o-DAP with formamidine acetate providing poor yields of IPs. In one case the parent substances were refluxed in 2-methoxyethanol, and in the other instance the heating at reflux of the parent substances was followed by vacuum distillation (63JOC1837). Reaction of o-DAP and potassium dithiofor-mate (48RTC29, 69RTC1263) afforded relatively poor yields of IP. The synthesis of... 

With )3-ketoesters, /3-ketoamides and )3-diketones, DAMN is converted into enamines, which can be cyclized purely by heating in an alcoholic solvent. The products are 2-substituted-4,5-dicyanoimidazoles (Scheme 2.1.5) [45], When DAMN reacts with formamidine, the initial condensation product (16)/(17) can form imidazoles either by loss of ammonia (when 4,5-dicyanoinnidazole is formed), or via an isomerization and subsequent cyclization which eliminates HCN to give 4-ainino-5-cyanoimidazole (18). With excess formamidine the latter product is converted into adenine. The intermediate amidines (16)/(17), as transient intermediates, react with aqueous ammonia to form (18), and with acetic acid to give (15) (R = R = H) [48, 50]. The transformation of (17) to (18) is a 1,5 bond formation (Scheme 2.1.6). 

This reaction was extended to the 2-methyl and 3-benzyl analogs of the starting material, making use of formamidine, acetamidine, and trichloro-acetamidine. Butanol proved to be the best solvent, and condensation times from 1 to 4 hr gave good to excellent yields. Neither the free bases nor the hydrochlorides of the amidines gave much product. It was thought that the free amidines were rather unstable under the conditions of the reaction and that the acetates furnished a steady supply of them.60... 

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