2-Aminopyridine, deriv with

Nitriles give good yields of 4-aminopyridine derivatives with y-dianions, as shown in reaction 15. Very hindered nitriles, such as t-BuCN, do not undergo this reaction. ... 

Of derivatives of compound 3, the zwitterions 245 react with DMAD if magnesium bromide is added to give aminopyridine derivatives (00H(53)265). Compounds such as 102 are opened by acid to give quaternary pyridinium salts (92LA885). There are various interconversions of 2-substituted triazolopyridin-3-ones into 1-substituted zwitterions. An example is the reaction of 246 (83BCSJ2969) the reverse conversion is also reported. 

Reaction of 2-aminopyridine and its 4-methyl derivative and diethyl alkylidenemalonates 356 at 175°C for 1.5-2.5h yielded 3-vinyl derivatives 358, after the isomerization of the exocyclic double bond in 357 (99ACS901). Reaction of 2-amino-4-methylpyridine and bis(2,4,6-trichlor-ophenyl) benzylidenemalonate in the presence of NEt3 afforded only non-cyclised product 359. 2-Aminopyridine and its 4-methyl derivative with diethyl benzylidene- and hexylidenemalonates at 190 °C did not give cyclized products (99ACS901, 99MI29). 

Reaction of 2-aminopyridine and its 3-, 4-, 5-, and 6-methyl derivatives with 3-chloro-3-trifluoromethyl-3-ethoxycarbonyl- and -2-cyanoacrylnitrils in CHCI3, sometimes in the presence of NEt3, afforded 4-oxo- and... 

Cyclocondensation of 2-aminopyridine and its 3-, 4-, and 5-methyl derivatives with ethyl 2-(bismethylthiomethylene)cyanoacetate in boiling BuOH for 5 h afforded 2-methylthio-4-oxo-4//-pyrido[l,2-u]pyrimidine-3-carbonitriles in 55-87% yields (96FES781). 

The tremendous scope of utilization of DMAP and PPY as catalysts has led to an active interest in the development of their polymeric analogs. The pioneering work was carried out by Hierl et al (8) and Delaney et al. (9). They attached 4-dialkyl-aminopyridine derivatives to poly(ethyleneimine) and found the modified polymers to be highly active catalysts for hydrolysis of p-nitrophenylcarboxylates. Since then, many research groups have reported the synthesis of polymers functionalized with 4-dialkyl-aminopyridine (10-18). 

Some unusual transformations will follow. The term unusual refers to unexpectedly smooth processes of H atom replacements obtained with (TMS)3SiH under radical conditions. Reaction (4.42) reports the replacement of a pyridinium moiety by hydrogen, with (TMS)3SiH under standard experimental conditions using t-BuOH as the solvent. In fact the two substrates (R = Me, Et) afforded 3-fluoro-2-aminopyridine derivatives in good yields [78], leaving the fluorine substituent untouched. 

The more recent 4-azaquinolizin-l-one synthesis by Katritzky etal. (81JCS(P1)1495) appears more versatile. A 2-ethoxycarbonyIpyrylium salt (275 Scheme 134) is allowed to react with the hydrazone of acetophenone or of a p-substituted acetophenone (276). The methyl group of the resulting 1-aminopyridine derivative (277) is acidic and, when treated with potassium carbonate, generates an anion which attacks the ethoxycarbonyl group to afford the 4-azaquinolizin-l-one derivative (278) in good yield. 

The synthesis of 6-substituted derivatives 626 was achieved via reaction of 2-substituted-5-aminopyridine-4-car-boxylic acids and formamidine acetate in boiling 2-methoxyethanol <1996J(P1)2221>. The pyrido[3,4- lpyrimidinone 628 was prepared by amination of the thioureido derivative 627 with diisopropylamine followed by cyclization in boiling DMF <2004FRP2846657>. Pyridine 627 was prepared from the corresponding 3-amino derivative with ethoxycarbonyl isothiocyanate in DMF. 

The diazepine (98) also reacted with base to give a 2-aminopyridine derivative but via a quite different process (71JOC2676). 

Cyclocondensation of 2-aminopyridine and its methyl derivatives with ethyl 2-oxocyclohexanecarboxylate in a mixture of polyphosphoric acid and phosphoryl chloride gave 1,2,3,4-tetrahydro-l 1 //-pyrido[2,l -b]-quinazolin-ll-one and its 6-, 7-, 8-, and 9-methyl derivatives (87JMC1543). 

Lappin20,21 studied the reactions of 2-aminopyridine and its monomethyl derivatives with methyl propiolate. In addition to the 2-oxo-2H-pyrido-[l,2-a]pyrimidines (22), the monoadducts (20) and/or the diadducts (21) were isolated. Only the pyrido[l,2-ci]pyrimidine was formed from 2-amino-6-methylpyridine. Lappin came to the conclusion that the addition step of the reaction is not stereospecific and that it leads to both the Z (19) and E (20) acrylates. In the next step the Z stereoisomer (19) readily undergoes cyclization due to its favorable geometric arrangement, thereby forming 22. The E acrylate (20) may react with another molecule of methyl propiolate to give the diadduct (21). Repetition of this work by Wilson and Bottomley22 led, in the case of 2-aminopyridine and 2-amino-5-methylpyridine, to the... 

Some 2-aminopyridine derivatives (107 and 108) were formed, also. Of the Schiff bases, only the benzaldehyde derivative reacted, yielding the 4-hydroxypyrido[l,2-a]pyrimidine (109), which was then oxidized with o-chloranil to the 4-oxo compound. 

The initiation by aromatic tertiary amines is affected by the type of substituent and its position in the ring. A series of meta-substituted pyridines show a higher activity than ortho- or para-substituted derivatives with electron-releasing substituents. 3-Aminopyridine is much more reactive than 2-aminopyridine and 3-methylpyridine is more effective than 2- or 4-methylpyridine 19). The strong electron-withdrawing substituent of 2-bromopyridine and its steric hindrance eliminate the effect of this amine. A 2,6-Dimethylpyridine was also found to display a steric effect. Thus, in the presence of this amine, the rate of copolymerization decreases by a factor of 4 compared with 3-methylpyridine 69). 

The condensation of 2-aminopyridine derivatives 64 with ethyl cya-noacetate gave amides 65, which were cyclized to 2//-pyrido[l,2-a] pyrimidin-2-ones 66 by the treatment of triethyl orthoformate and acetic anhydride (90IZV229). 

Different malonyl-a-aminopyridines 110 (R = H, Me) were prepared from 2-aminopyridine and its methyl-substituted derivatives with diethyl 2-substituted malonates at 160-180°C with continuous distillation of the ethanol formed, or with bis(2,4,6-trichlorophenyl) 2-substituted malonates in acetone under reflux, or at ambient temperature in the presence of triethylamine (91T675). 

Reaction of 2-aminopyridines with acrylic acid or methacrylic acid in boiling water for 2-20 hours gave betaine hydrates 262 (R3 = H) in 11-88% yields (Scheme 20) (92KGS80). When 2-aminopyridine reacted with methyl metharylate in acetic acid for 24 hours or 2-aminopyridine and its 5-bromo and 5-chloro derivatives reacted with acrylic acid in boiling toluene for 24 hours or 2-aminopyridine reacted with crotonic acid in boiling toluene for 20 hours, 3-(2-pyridylamino)propionic acid derivatives 263 were the products. When 5-chloro-2-aminopyridine reacted with acrylic... 

Other related distonic superelectrophiles (200-201) were also shown to provide acyl-transfer products with benzene, and in the case of the aminopyridine derivative (202) intramolecular reaction produces the indanone (eq 69). 

The 4-aminopyridine derivative 92, prepared from the reaction of ethyl benzoylacetate and malononitrile dimer 91, undergoes the coupling reaction with aromatic diazonium salts to afford azo derivatives such as 93. Under refluxing conditions in ethanolic sodium hydroxide, these azo compounds cyclize to pyrido[3,2-f]pyridazines and pyrido[3,2-r]-pyridazino[2, 3 - ]quinazolines (Scheme 15) <2005AP329>. 

The almost exclusive ring closure at the a-position carries over to other electrophilic reactions of substituted 3 -aminopyridine derivatives. For example, the condensation of 3-aminopyridine with ethoxy-methylenemalonic ester (EMME) in dilute solution in boiling Dowtherm A gave the 1,5-naphthyridine 190.425,426 The only exception to date is that of 3-aminopyridine A -oxide which, as expected,... 

Intramolecular acylations of the Friedel-Crafts type will also take place with 3-aminopyridine derivatives but usually require either stringent conditions or the presence of further activating groups in the pyridine nucleus. The report that the acid 191 can be converted into... 

An unusual replacement of a pyridinium moiety in 70 by hydrogen has also been successful with (TMS SiH under normal radical conditions. In fact, the two substrates in equation 31 afforded 3-fluoro-2-aminopyridine derivatives in good yields80. 

The [l,2,4]triazolo[l,5- ]pyridine system is usually constructed by the closure of the triazole ring either by oxidative formation of the NN bond or by condensation of the N-aminopyridine derivatives . Various compounds 78 were obtained by the oxidation of the amidine 77 with Mn02 (Scheme 47) <2003IJB2901, 2005ARK(xiii)21>. A dehydrative cyclization by treatment of formamidoximes 79 with trifluoroacetic anhydride (TFAA) has been used in the synthesis of 80 (Scheme 48), which are key building blocks in the preparation of DPP (IV) inhibitors <2005EJ03761, 2006JME3614>. 

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