3.4- Diaminopyridine

Cautiont The hromination and nitration steps should be carried out in a well-ventilated hood. 

2-Amino-5-bromopyridine. In a 2-1. three-necked flask equipped with stirrer, dropping funnel, and condenser is placed a solution of 282 g. (3.0 moles) of 2-aminopyridine (Note 1) in 500 ml. of acetic acid. The solution is cooled to below 20° by immersion in an ice bath, and 480 g. (154 ml., 3.0 moles) of bromine dissolved in 300 ml. of acetic acid is added dropwise with vigorous stirring over a period of 1 hour. Initially the temperature is maintained below 20°, but after about half the bromine solution has been added it is allowed to rise to 50° to delay as long as possible the separation of the hydrobromide of 2-amino-5-bromopyridine. At 50° the hydrobromide usually begins to crystallize when about three-quarters of the bromine has been added. When addition of bromine is completed, the mixture is stirred for 1 hour and is then diluted with 750 ml. of water to dissolve the hydrobromide. The contents of the flask are transferred to a 5-1. beaker and are neutralized, with stirring and cooling, by the addition of 1.2 1. of 40% sodium hydroxide solution. 

The precipitated 2-amino-5-bromopyridine, contaminated with some 2-amino-3,5-dibromopyridine, is collected by filtration and, 

3-Diamino-5-bromopyridine (Note 8). A 100-ml. flask fitted with a reflux condenser is charged with 10.9 g. (0.05 mole) of 2-amino-5-bromo-3-nitropyridine, 30 g. of reduced iron, 40 ml. of 95% ethanol, 10 ml. of water, and 0.5 ml. of concentrated hydrochloric acid (Notes 9 and 10). The mixture is heated on a steam bath (Note 11) for 1 hour, and at the end of this period the iron is removed by filtration and is washed three times with 10-ml. portions of hot 95% ethanol. The filtrate and washings are evaporated to dryness, and the dark residue is recrystallized from 50 ml. of water, 1 g. of activated carbon being used and the mixture being filtered while hot. The charcoal is washed with hot ethanol to avoid losses. 2,3-Diamino-5-bromopyridine crystallizes as colorless needles, m.p. 163°. The yield is 6.5-7.1 g. (69-76%). 

3-Diamino pyridine (Note 12). In an apparatus for catalytic hydrogenation (Note 13) 56.4 g. (0.3 mole) of 2,3-diamino-5-bromopyridine suspended in 300 ml. of 4% sodium hydroxide solution is shaken with hydrogen in the presence of 1.0 g. of 5% palladized strontium carbonate (Note 14). When absorption of hydrogen is completed, the catalyst is removed by filtration, and, after saturation with potassium carbonate (about 330 g. is required), the resulting slushy mixture is extracted continuously with ether until all the precipitate completely disappears (usually about 18 hours, but this depends on the efficiency of the extraction apparatus). The ether is removed by distillation, and the residue of crude 2,3-diaminopyridine is recrystallized from benzene (about 600 ml. is required) using 3 g. of activated charcoal and filtering rapidly through a preheated Buchner funnel. The yield of 2,3-diaminopyridine, obtained as colorless needles, m.p. 115-116°, pKft 6.84, is 25.5-28.0 g. (78-86%) (Note 15). 

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After ca. 30 min, when the chloroform had evaporated, fluorescent chromatogram zones appeared on a dark background on excitation with long-wavelength UV light (X = 365 run) 2,3-diaminonaphthalene (h/ f 70-75), red and 2,3-diaminopyridine (h/Jf 55-60), blue. The detection limits were 3 ng substance per chromatogram zone. 

Fig. 1 Fluorescence scans of a chromatogram track with 60 ng each of 2,3-diaminopyridine (Ijl and 2,3-diaminonaphthalene (2) per chromatogram zone ...

A differently fused pyrrolopyridopyrazine is obtained from 2,3-diaminopyridine, an acylpyruvic acid, and oxalyl chloride (Scheme 59) <2000CHE1114> and imidazopyridopyrazines such as 250 have been prepared by acylation of o-aminohalogenopyridines with carbonylimidazole dimer (Equation 74) <2001TL4297>. 

By this method of preparation 2,3-diaminopyridine is obtained in 26-43% yield from the readily available 2-aminopyridine. The intermediates 2-amino-S-bromopyridine and 2-amino-S-bromo-3-nitropyridine are prepared in higher yields than previously recorded. 

Methods of preparation of 2,3-diaminopyridine which involve the reduction of 2-amino-3-nitropyridine are laborious. The material is obtained in yields of less than 10% by nitration of... 

Diaminopyridine has been prepared by reduction of 2-amino-3-nitropyridine with iron and aqueous acidified ethanol,3 tin and hydrochloric acid,6 or stannous chloride and hydrochloric acid,6 by catalytic reduction of 3-amino-2-nitropyridine,6 by reduction of 3-amino-2-nitropyridine,7 2-amino-5-chloro-3-nitro-pyridine,8 or 2-amino-5-bromo-3-nitropyridine 4 with sodium hydroxide solution and an aluminum nickel alloy, and by catalytic reduction of 2-amino-5-bromo-3-nitropyridine.4 Animation of... 

Mercaptoacetic acid could be used as a versatile synthon for the synthesis of 17/,3//-thiazolo[3,4-tf]benzimidazole-type compounds <1996FA279, 1997FA673>. For instance, 2,3-diaminopyridine and 2-mercaptoacetic acid were reacted in a three-component reaction with a suitable carbonyl compound and provided the 17/,3//-thiazolo[3,4- ]-imidazo[4,5- ]pyridines 451 (Equation 212) <1994FA345>. 

FIGURE 3 Electropherogram of (di)aminopyridine standards. Electrophoretic conditions capillary 67 cm total length (60cm effective length), 50 pm ID BGE 100 mM sodium acetate buffer, pH 5.15 voltage 20 kV detection 240 nm. 4-AP 4-aminopyridine 2-AP 2-aminopyridine 3-AP 3-aminopyridine 3,4-DAP 3,4-diaminopyridine 2,3-DAP 2,3-diaminopyridine 2,6-DAP 2,6-diaminopyridine NEDA N-(l-naphthyl)ethylenediamine (internal standard). (Reprinted from reference 125, with permission.)... 

The above examples report perhaps the most well used routes to imidazo[4,5-3]pyridines however, there are many other less well known methods. For example, treatment of 2,3-diaminopyridines with aryl aldehydes and subsequent oxidation with sulfur affords the corresponding imidazo[4,5-/ ]pyridines in good yield <1996CHEC-II(7)283>. A catalytic Fe(iii)/Fe(ll) redox cycle approach to imidazopyridines has been reported (Equation 33) <2000S1380>. A hypervalent iodine oxidative rearangement of 2-aminopyridinecarboxamides has also been reported <2001S541>. Treatment of 2-amino-4,6-diphenyl-3-pyridinecarboxamide 123 with iodobenzene diacetate (IBD) in KOH/MeOH afforded the pyridin-2-one 124 (Equation 34). 

Similarly, when dialkyl acetylenedicarboxylates were condensed with 2,3-diaminopyridine in ethanol, the 2-carboxy-carbonylmethylene-l,2-dihydro-4/f-pyrido[2,3- ]pyrazin-3-ones 33 were obtained. The isomers 34 were formed when acidified ethanolic solution was employed <1995JHC1071>. 

Reaction of 2,3-diaminopyridine with ethyl 2,3-dibromopropionate in boiling DMF in the presence of K2CO3 provided the pyridopyrazine-2-carboxylate 205 as the major product along with a mixture of tetrahydro isomers 203 and 204. The small quantity of isomer 203 was attributed to spontaneous oxidation to the product 205 (Equation 53) <2002T5241>. 

The application of Schiff base chemistry to the synthesis of heterophanes possessing diverse subunits has been reviewed in part (82MI52202, B-79MI52201). An example of this procedure is the treatment of (19) with 2,3-diaminopyridine, with or without metal ion templation, to give (20) as an isomeric mixture (75MI52200). 

Electrochemical oxidation of 2-, 3-, and 4-aminopyridines as well as 2,6-diaminopyridines and aminopicolines was studied in CH3CN-LiC104 by means of RDE voltammetry.422 Also, the electrochemical oxidation of 3-aminopyridine, 2,3-diaminopyridine, and 2,6-diaminopyridine has been investigated in aqueous solutions in the pH range 0.7-13 at platinum and carbon paste solid electrodes.423 A reaction scheme for the oxidation of aminopyridines was proposed on the basis of the voltammetric results, but the products of the oxidations were not identified. 

Tisler and co-workers prepared 3-benzamido-4//-pyrido[l,2-a]-pyrimidin-4-ones 180 (R = H) in the reaction of 2-aminopyridines (R1 = H,3-NH2,4-Me) and 3-ethoxy-2-benzamidoacrylate 179 in refluxing acetic acid (90JHC359). From 2,3-diaminopyridine a condensed pyr-... 

As noted already, the reactions of oc,(3-unsaturated ketones with or /zo-diamines are often accompanied by various rearrangements and side processes. For instance, the o-PDA condensation with chalcone in the presence of an acid catalyst or during overheating of the reaction mixture produces a final product of 2-phenylbenzimidazole [2, 7] a similar phenomenon is also observed for 2,3-diaminopyridine [54]. Owing to the existence of much more suitable approaches to the synthesis of 2-aryl derivatives of benzimidazole and their heteroannelated analogues (e.g., proceeding from diamines and acids or aldehydes [121]), such a trend in the interaction of chalcones with diamines is unlikely to have any application for this purpose. 

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