6-Amino-5-cyanopyridines, reactions

In several cases the application of other basic catalysts is described, but such reactions often are followed by numerous side reactions or proceed in another direction. For example, in the reaction of malononitrile 107 with dimethylami-nochalcone 111 in the presence of pyrrolidine as the catalyst, instead of the expected cyanopyridines being formed the heterocycle 5-amino-7-(pyrrolidin-l-yl)-l,6-naphthyridine-8-carbonitrile 112 [118] is produced (Scheme 3.34). 

The reactions using some strong bases (sodium hydroxide [120, 121, 122, 123, 124] or sodium ethoxide [125]) are accompanied by nucleophilic substitution of the amino group at the 2 position of the cyanopyridine (Scheme 3.35). 

The reaction products of the treatment of a, 3-unsaturated ketones with malononitrile in most cases are the expected derivatives of 2-amino-3-cyanopyridine. But an alternate direction with the formation of carbocyclic compounds 120 was described [128]. It is clear from structure 120 that two molecules of unsaturated ketone 5 and 1 equiv of malononitrile 107 are involved in the reaction (Scheme 3.37). 

The pyridopyrimidines (288) have been prepared by reaction of A,A -dibenzylidenephenyl-methanediamines with 2,6-diaryl-4-piperidones <83S564>. The C-nucleoside analogue (289) was obtained by the cyclization of a- and /l-5-ribosyl-4-amino-3-cyanopyridine with HC(0Et)3-Ac20 followed by treatment with saturated methanolic ammonia, whereas compound (290) was prepared by conversion to the amide before cyclization <92M1716-01). 

The octahydroquinolines 24 and decahydroacridines were obtained from dimedone. On montmorillonite KSF clay, acridine derivatives 25 were obtained. Reaction of arylidenemalononitriles with cyclic ketones gave 2-amino-3-cyanopyridines 26. Reaction of diphenylamine and dicarboxylic acids or arylacetic acids was catalyzed by zinc chloride to give acridines. Pyrimido[4,5-Z>]quinolines 27 were synthesized. ... 

Marzinzik and Felder [34] synthesized a 3-cyanopyridine via the reaction of a polymer-bound enone with 3-amino-crotonic acid nitrile derived in a Thorpe reaction from acetonitrile and potassium terf-butoxide (B b, d Fig. 6.22) [26]- The product was obtained in 46 % yield, and with a HPLC purity of 78 %. 

Several ring-fused tetrazole compounds have been reported. 2-Methyl-3-cyanopyridines were converted into their corresponding 2-azidomethyl derivatives, which underwent intramolecular cycloaddition reactions to give 3-(tetrazol-5-yl)pyridines 186 <04TL9127>. Fused tetrazole derivatives 187 were obtained via tandem cycloaddition and yV-allylation reactions <04JOC1346>. Expeditive synthesis of homochiral fused tetrazole piperazines 188 from 3-amino alcohols has been reported <04TL3725>. A novel Ugi-five-center-four-component reaction (U-5C-4CR) of aldehydes, primary amines, trimethylsilyl azide and 2-isocyanoethyl tosylate afforded tetrazolopiperazine type compounds <04TL6421>. 

Nitriles can also be substituted for formamide. Benzonitrile and 2-aminobenzonitrile, autoclaved at 200°C, gave a moderate yield of 4-amino-2-phenylquinazoline (see 1). This reaction resembles, and is competitive with, the dimerization of aminonitriles discussed above it also proceeds by a similar mechanism. Other examples are the condensation of 3-cyanopyridine with 2-amino-3-cyanopyridine to give 2-(3-pyridyl)-4-aminopyrido[2,3-d]-pyrimidine (see 3) and of 5-cyano-l-methyl-4-aminoimidazole (see 18) with... 

In an unusual reaction, 2-acetamido-3-cyanopyridine, when refluxed with hydroxylamine in toluene for 1 hr, gave a low yield of 4-amino-2-methyl-pyrido[2,3-d ]pyrimidine 3-oxide.13 5... 

Derivatives of 2-amino-3-cyanopyridines 154 have been synthesized from the reaction of arylidenemalononitriles 59 with a-methylene ketones in the presenee of ammonium aeetate and traces of solvent under both classical heating for 5 h in... 

A simple and efficient synthesis of 2-amino-3-cyanopyridines 326 was carried out through the reaction of arylidenemalononitriles 59 with cyclic ketones 325. The reaction under MWI in the presence of ACONH4, without or with a trace of solvent, gave 326 in 42 78% yields within 3.5-4.5min (Scheme 66), while the synthesis required 5.5-6 h, in refluxing benzene, to give lower yields (46-55%) (98JCR(S)330). 

In 2014, Odom and coworkers reported a titanium-catalyzed synthesis of 2-amino-3-cyanopyridines (Scheme 3.41) [89]. The reactions were performed in a one-pot manner with two manipulation steps. Firstly, titanium-catalyzed alkyne iminoamination and generation tautomers of 1,3-diimines. Then, 2-amino-3-cyanopyridines were formed in good to modest yields after treatment with base (DBU) and malononitrile. A Dimroth rearrangement mechanism for 2-aminopyridine formation was proposed based on the isolation of a 2-imino-l,2-dihydropyridine intermediate which undergoes rearrangement under the reaction conditions. 

Several derivatives of racemic amino-sugars have been synthesized from heterocyclic precursors. Thus, the four isomeric methyl 3-amino-3,4-dideoxy-DL-pentopyranosides have been derived from dihydro-(4 )-pyran, as indicated in Scheme 29, furfural has been converted into derivatives of 6-acetamido-6-deoxy-DL-mannopyranose, ° and 3-cyanopyridine has been transformed into the racemic nojirimycin (5-amino-5-deoxy-DL-glucopyranose) derivative (122) by the sequence of reactions outlined in Scheme 30. ... 

A few 3-cyanopyridines have been prepared, in 40-50 per cent yield, by reaction of a 3-pyridyl diazonium salt with potassium cuprocyanide or cuprous cyanide2i8, 755-7 Though 2- and 4-aminopyridines have been converted into 2- and 4-halogenopyridines via the diazonium reaction, the ready reaction of the 2- and 4-pyridyldiazonium ions with nucleophiles present in the solutions in which they are formed makes their use in cyana-tion difficult if not impossible. The difference in ease of diazotization between a 2- and a 3-aminopyridine permits the conversion of 2,5-diaminopyridine into 2-amino-5-cyanopyridine by diazotization in dilute acid is. The easier diazotization (p. 359) of 4-aminopyridine 1-oxides and the greater stability... 

Full details have been published of the synthesis of pyridines derived from the 1,5-dicarbonyl compounds resulting from the reaction of -ketoketene dithioacetals with the carbanions obtained by deprotonation of methyl ketones. 5 There have been two reports of the synthesis of pyridines from enamines and malononitrile.26,27 This route is exemplified by the conversion of the readily available enamines (10 Z=0 or S) into the 2-amino-3-cyanopyridines (11) ... 

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