2- Aminopyridine preparation

Tripelennamine can be prepared as follows 2-aminopyridine, prepared by the action of sodamide on pyridine, is reacted with P-dimethylaminoethyl chloride in the presence of sodamide, and the resulting 2-[2-(dimethylamino) ethylamino] pyridine is subsequently condensed with benzyl bromide in the presence of sodamide. The corresponding hydrochloride salt is obtained from the base by treatment with hydrogen chloride in an organic solvent. 

Cognate preparation. 3-Aminopyridine. Prepare a cold sodium hypobromite solution from 32 g (10 ml, 0.2 mol) of bromine and 25 g (0.62 mol) of sodium hydroxide in 250 ml of water. Add in one portion 20 g (0.163 mol) of finely powdered nicotinamide (Expt 6.169) and stir vigorously for 15 minutes. Warm the solution in a water bath at 75 °C for 45 minutes. Isolate the crude product by continuous ether extraction (Section 2.22) of the cooled reaction mixture after saturation with sodium chloride. Dry the extract over potassium hydroxide pellets and remove the ether. Crystallise the dark residue from a 4 1 mixture of benzene-light petroleum (b.p. 60-80 °C) with the aid of decolourising charcoal. The yield of almost colourless product, m.p. 63 °C, is 9.3 g (61%). 

Fluoropyridine. This isomer can be prepared in 54—81% yield by dia2oti2ation of 4-aminopyridine in anhydrous hydrogen fluoride (370,371,400). Eree 4-fluoropyridine readily undergoes self-quaterni2ation to give pyridyl pyridinium salts (401) stabili2ation can be effected as the hydrochloride salt (371,400). Numerous 4-fluoropyridinium salts, eg, 4-fluoro-l-methylpyridinium iodide, have been converted to novel penicillins (387,402). 

Ethoxymethylene- and aminomethylene-amino intermediates are also of use for preparation of 4-ones and 4-imines, e.g. (121) — (122) — (123) from o-aminopyridine esters (78KGS1671) and nitriles (e.g. 75JCS(P1)2182>. 

Dihydropyrido[2,3- /]pyrimidines have also been prepared from 3-acylaminomethyl-2-aminopyridines (53JA656). 

Amine oxides, prepared to protect tertiary amines during methylation and to prevent their protonation in diazotized aminopyridines, can be cleaved by reduction (e.g., SO2/H2O, 1 h, 22°, 63% yield H2/Pd-C, AcOH, AC2O, 7 h, 91% yield Zn/HCl, 30% yield). Photolytic reduction of an aromatic amine oxide has been reported [i.e., 4-nitropyridine A-oxide, 300 nm, (MeO)3PO/CH2Cl2, 15 min, 85-95% yieldl. ... 

Thiophenealdehyde has been used in the reductive alkylation of 2-aminopyridine and 2-aminopyrimidine. 2-Arylamino-4- (2-thienyl )thiazoles have been prepared by the reaction of 2-acetylthio-phene with A-arylthioureas in the presence of iodine, ... 

All existing syntheses of pyrido[4,3-d]pyrimidines from pyridines build up the pyrimidine ring from a 3-substituted 4-aminopyridine by methods closely similar to those applied for the other systems (routes i and u). The preparation of suitable 4-aminopyridines presents some... 

The first amination of a halogenopyridine involving a rearrangement was carried out by Levine and Leake in 1955 in an attempt to prepare 3-phenacylpyridine. When 3-bromopyridine (27, X = Br) was allowed to react with sodium amide in liquid ammonia in the presence of sodio-acetophenone, the reaction mixture obtained consisted chiefly of amorphous nitrogenous material from which only 10% of 4-aminopyridine (34, Y = NH2) and 13.5% of 4-phenacylpyridine were isolated. 

Tire use of nitro synthons for the preparation of nitronaphthyridines and their derivatives has been extensively studied and has found widespread application. Most known nitro compounds have been synthesized using these methods and nearly all of them use an aminopyridine or (substituted amino)pyri-dine as starting material for the construction of the nitronaphthyridine ring. Tliese synthetic methods can be divided into four categories. 

Methyl-4//-pyrido[l,2-n]pyrimidin-4-ones were also prepared in the reaetion of 2-aminopyridines and ethyl 3-methoxy-2-butenoate in PPA at 80-85 °C for 3h (93MI2). 

A one-pot synthesis of thiohydantoins has been developed using microwave heating [72]. A small subset of p-substituted benzaldehydes, prepared in situ from p-bromobenzaldehyde by microwave-assisted Suzuki or Negishi reactions, was reacted in one pot by reductive amination followed by cyclization with a thioisocyanate catalyzed by polystyrene-bound dimethyl-aminopyridine (PS-DMAP) or triethylamine, all carried out under microwave irradiation, to give the thiohydantoin products in up to 68% isolated yield (Scheme 16). 

Alkali metal derivatives of 2-(trimethylsilyl)aminopyridines can be further derivatized by insertion of 1,3-dicyclohexylcarbodiimide. Functionalized guani-dinates are formed in this reaction via a 1,3-silyl shift. Scheme 170 illustrates the reaction sequence as well as the preparation of an aluminum complex of the modified ligand, which exhibits pseudo jS-diketiminate binding of the metal center, thus exemplifying the coordinative versatility of this new multi-N-donor system. ... 

The regioselective halogenation of pyridinium-A -(2 -pyridyl)aniinide 7 with N-halosuccinimides, combined with a reduction of the N-N bond, provides a convenient preparation of 5-halo- and 3,5-dihalo-2-aminopyridines 8 <95T(51)8649>. 

Directed metallation continues to be developed as a convenient method for regiospecific substitution of pyridines. A mild and general procedure for the preparation of structurally diverse 4-alkyl-2-aminopyridines 37 involves the lithiation/alkylation of aminopyridine derivative 36 <96JOC(61)4810>. 

Pyridine-based N-containing ligands have been tested in order to extend the scope of the copper-catalyzed cyclopropanation reaction of olefins. Chelucci et al. [33] have carefully examined and reviewed [34] the efficiency of a number of chiral pyridine derivatives as bidentate Hgands (mainly 2,2 -bipyridines, 2,2 6, 2 -terpyridines, phenanthrolines and aminopyridine) in the copper-catalyzed cyclopropanation of styrene by ethyl diazoacetate. The corresponding copper complexes proved to be only moderately active and enantios-elective (ee up to 32% for a C2-symmetric bipyridine). The same authors prepared other chiral ligands with nitrogen donors such as 2,2 -bipyridines 21, 5,6-dihydro-1,10-phenanthrolines 22, and 1,10-phenanthrolines 23 (see Scheme 14) [35]. 

Aminopyridine was also reacted with iV,./V -bis(l-chloroalkylidene)urea derivatives <1995UKZ37> or 1-chloro-alkylisocyanates <1995UKZ63> to prepare pyrido[l,2- ][l,3,5]triazin-4-ones. 

The photocyclization of enamides has been widely employed in the construction of heterocyclic systems the N-acryloyl-2-aminopyridines 37, for example, are converted on irradiation to the lactams 38.36 Numerous benzylisoquinoline alkaloids have been prepared using this approach, and in particular, the syntheses of benzo[c]phenanthridine alkaloids have been reviewed.37 Thus, irradiation of the [Z]-l-ethylidene-2-benzoyltetra-hydroisoquinoline 39 affords the corresponding 8-oxoberberine 4038 competing photoisomerization to the E-isomer is observed but cyclization occurs only via the Z-isomer. Examples of syntheses of Amaryllidaceae and indole alkaloids have also been reported. In this way, the precursor 41 of ( )-lycoran has been obtained by oxidative cyclization of the enamide 42.39... 

The parent heterocycle of pyrido[2,3-e][l,2,4]triazine and its phenyl derivative 39 were prepared (89JHC475) by cyclization with polyphos-phoric acid of 3-acyIhydrazino-2-aminopyridines 36, obtained by reduction of the corresponding 3-acylhydrazino-2-nitropyridines 35. Compounds 35 were obtained from 3-fluoro-2-nitropyridine 34 either by reaction with benzoylhydrazine or by reaction with hydrazine and subsequent for-mylation of the initially formed 3-hydrazino-2-nitropyridine 38. Attempts to prepare 38 from 3-chloro-2-nitropyridine gave 2-hydrazino-3-chloropyridine 37. These results could be explained by semiempirical calculations (CNDO and MNDO calculations). 

Rifaximin (4-deoxy-4/-methylpyrido[l, 2 -l,2]imidazo-[5,4-c]rifamycin SV, fig. 2) is a synthetic product designed to modify the parent compound, rifamycin, in order to achieve low GI absorption while retaining good antibacterial activity [37]. It is a rifamycin SV derivative, prepared by condensing 2-aminopyridine derivatives to 3-bromorifamycin S (fig. 3) [37-39]. This pyridoimidazo rifamycin SV derivative, which proved to be stable in gastric juice for 24 h, displays a zwitterionic nature at physiological pH [38]. 

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. 

Irnidazo[ 1,2-tf ]py ridines were covered in CHEC(1984) <1984CHEC(6)613> along with others imidazoles fused to six-membered rings and they were reviewed together with imidazo[l,5- ]pyridines in CHEC-II(1996) <1996CHEC-II(8)249>. The chemical literature on this heterocycle is very abundant, due to its easy synthesis (most of the preparations use readily available 2-aminopyridines) and to the very broad spectrum of bioactivities displayed by many derivatives. A simple Beilstein search on the fully conjugated heterocycle (free sites everywhere) disclosed ca. 3000 hits for the past decade. Therefore, this chapter cannot be exhaustive in view of space limitations, but will mainly focus on the original synthetic methods that have appeared in the last decade. 

A lot of methods are available for the synthesis of this heterocycle, and most of them rely on the formation of the five-membered ring. In this section, only the methodologies of reasonable scope will be reported. The most classical method involves the cyclocondensation of 2-aminopyridine with an a-halo carbonyl compound. Due to the broad availability of the required substrates and the efficiency of this cyclocondensation, it continues to be the method of choice to prepare this heterocycle. New examples highlighting the generality of this reaction are collected in Table 14. 

Pyridylaminomethylenemalonates (262) were prepared in over 90% yields in the reactions of 2-aminopyridines, ethyl orthoformate, and dialkyl malonates at 130°C for 3-6 hr (73GEP2227651 87SC549). 

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