2- Aminopyridine sulfonation

Ozone oxidation of 6-aryl-2-methylthiopyrido[2,3-methyl sulfone with /ra j-4-aminocyclohexanol afforded the amino pyridopyrimidinone derivative 176 <2002W02002018380>. Amination of 6-dimethoxyphenyl-8-ethyl-2-methylthiopyrido[2,3-t7 pyrimidin-7-one with 4-aminopyridine and LiNH2 in THF at 50°C produced the 2-[(4-pyridyl)amino] derivative 177 <2003W02003027110>. 

Aminopyridine and l-methyl-2-pyridone are sulfonated under milder conditions (H2S04-S03, 140°C) in the 5-position. 2,6-Di-r-butylpyridine is converted into the 3-sulfonic acid under mild conditions (S02-S03, 0°C) because reaction of S03 at the nitrogen atom is prevented sterically thus, reaction occurs on the free base, under conditions where this is the majority species. 

Benzeneselenenyl halides, 26 Camphor- 10-sulfonic acid, 62 Dicyclohexylcarbodiimide-4-Dimethyl-aminopyridine, 107 Hydrofluoric acid-Acetonitrile, 188 Thiophenol, 297 Lithiation (see Metallation)... 

Sulfonylation of 2-aminopyridine occurs at the 5-position under fairly harsh (140 °C) conditions of sulfur trioxide in sulfuric acid. Subsequent C-3 bromination under mild conditions affords 89. Similarly 2-hydroxy nicotinic acid when subjected to stoichiometric 30% oleum at 140 °C gave sulfonic acid 90 in 90% yield (Equations 32 and 33) <20020PD767>. 

Sulfonation of 2-aminopyridine gives the 5-sulfonic acid exclu-sively.56,109,110 3-Aminopyridine reacts with chlorosulfonic acid to give 3-amino-2-pyridinesulfonic acid (44).103,111 4-Amino-3-pyridine-sulfonic acid is obtained from 4-aminopyridine.112 Arsonation of... 

Kanbara has since generated a family of poly(iminoarene)s by reaction of 1,3-dibromo-benzene, 4,4-dibromodiphenyl ether, 2,6- and 3,5-dibromopyridines, 2,4-dibromothiophene, and l,l -dibromoferrocene with a variety of bifunctional arylamines [229]. In many cases, no polymer was obtained, but for polymerizations involving dibromobenzene and 2,6-dibromopyridine, materials with JVfn values of over 10,000 were obtained. Spectral data were provided for poly(2,6-aminopyridine) and a polymer made from dibromobenzene and a dia-rylamino sulfone. These authors have also investigated nickel catalysts for the polymerization of diamines with dichloroarenes, but the materials generated had molecular weights below 10,000 in most cases [230]. 

Pyridones, aminopyridines, and diazines with two strongly activating substituents, readily undergo nitration, sulfonation, and halogenation (reactivity approximately that of benzene). 

Figure 8 Electrochromatographic separation of aromatic acids (a) and anilines (b) on monolithic capillary columns [58], Conditions butyl methacrylateethylene dimethacrylate stationary phase with 0.3 wt% 2-acrylamido-2-methyl-1 -propane-sulfonic acid pore size, 750 nm UV detection at 21 5 nm voltage, 25 kV pressure in vials, 0.2 MPa injection, 5 kV for 3 s. (a) Capillary column, 30 cm (25 cm active length) x 100 pm i.d. mobile phase, acetonitrile-5 mmol/L phosphate buffer, pH 2.4 (60/40, v/v). Peaks 3,5-dihydroxybenzoic acid (1), 4-hydroxybenzoic acid (2), benzoic acid (3), 2-toluic acid (4), 4-chlorobenzoic acid (5), 4 bromobenzoic acid (6), 4-iodobenzoic acid (7). (b) Capillary column, 28 cm (25 cm active length) x 100 pm i.d. mobile phase, acetonitrile/10-mmol/L NaOH, pH 12 (80/20, v/v). Peaks 2-aminopyridine (1), 1,3,5-collidine (2), aniline (3), AAethylaniline (4), N-butylaniline (5). (Reprinted from Ref. 49, with permission.)...

Problem 31.11 2-Aminopyridine can be nitrated or sulfonated under much milder conditions than pyridine itself substitution occurs chiefly at the 5-position. Account for these facts. 

In the large scale synthesis of the successor to Viagra described in the last chapter a short synthesis of the pyridine 23 replaced a much longer laboratory synthesis that used a similar sequence. The amino group in available 2-aminopyridine 15 directed sulfonation and bromination to give 17 and then, its work done, was replaced by the OH group 18. 

Abbreviations 2-AP = 2-aminopyridine a-La = a-lactoalbumin P-Lg = P-lacto-globulins CAPS = 3-[cycloheylamino]-1-propane-sulfonic acid CN = caseins DMF = dimethylformamide HIBA = a-hydroxyisobutyric acid Hx = Hypoxanthine HxR = inosine ID = inner diameter IMP = inosine 5 -monophosphate MeOH = methanol MHEC = methylhydroxycellulose PA = polyacrylamide PEG = polyethylene glycol PBS = phosphate buffered saline PTFE = polydetrafluoroethylene. 

Corrosion inhibitors for mineral oils include alkyl imidazoles, amines, aminopyridines, quaternary ammonium salts, alkyl sulfonates, borate esters, hydroxy amines, naphthenic acids, phosphate esters, and stearates. 

The use of dry aryldiazonium salts of naphthalene-1-sulfonic [70], naphthalene-1,5-disulfonic [70], ZnCl2 complex [70], hexafluorophosphoric or tetrafluoroboric acid [61] in non-aqueous medium under as mild as possible reaction conditions is substantial to reach higher yields of biaryls. An alternative method for non-aqueous GBH reaction is the aprotic diazotation of aromatic amines with alkyl nitrites such as butyl or pentyl nitrite with subsequent arylation of aromatic compound, as demonstrated by Cadogan [71,72]. This method is realized by simple heating the mixture of aromatic amine, alkyl nitrite and liquid arene at an elevated temperature. When a mixture of 3-aminopyridine (46), benzene and pentyl nitrite is heated at reflux, 3-phenylpyridine (47) is obtained with a 55% yield [71], Scheme 16. 

Metal-acid solutions have been employed in the reduction of nitropyridines to aminopyridines. Zinc dust and acetic acid have been used in the preparation of 3-amino-l-benzyl-4-pyridone or 3-amino-l-benzyl-S-iodo-4-pyridone from the corresponding 3-nitro derivatives. Tin or iron in acids is more popular. For example, 3-amino-2-(o-bromobenzyloxy)-pyridine is obtained by the reduction of 2-(o-bromobenzyloxy)-3-nitropyridine using iron and hydrochloric acid. Various ferrous salts have also been effective reducing agents. Several derivatives of phenyl 5-amino-2-pyridyl sulfide (K-16) (or the sulfone)are... 

When pyridine-4-siilfonic acid is heated with ammonium hydroxide or with an alkylamine in the presence of a maii amount of zinc chloride it gives 4 minopyridine and 4-alkylaminopyiidine, respectively. 4-Amino-2,6-di- -butylpyridine is obtained on heating 2,6-di-r-butylpyiidine-4-sulfonic acid with aqueous ammonia in a small sealed tube. The cyano group in the 4-position is also labile thus 4-cyanopyridinium methiodide reacts with ammonium hydroxide to give 4-aminopyridine methiodide (IX-28). °... 

Chloromethanesulfonyl chloride reacts with 2-aminopyridine to give 2-(chloromethylsulfonamido)pyridine. AT-2-Pyridylalkanesulfonamides are formed from 2-ammopyridine and an alkane sulfonic acid these sulfonamides are amphoteric. ... 

Miscellaneous reactions of aminopyridines with sulfur derivatives have been observed. p-Chlorophenyl hydroxymethylsulfone reacts with 2-aminopyridine to give p-chlorophenyl-2-pyridylaininomethyl sulfone [(IX-90). ... 

When 3-aminopyndine is diazotized with hydrochloric acid and sodium nitrite and then treated with acetic acid containing sulfur dioxide and cupric chloride, 3-pyridine ulfonic acid can be isolated. Similarly, 4-aminopyridine-l-oxide gives 4-pyridinesulfonic acid-1 -oxide, but the 2-isomer gives very poor yields of the corresponding sulfonic acid. The preparations and reactions of various 3-pyridinediazonium salts have been reported. 3-Amino-2,6-lutidine... 

---