2-Amino-6- nicotinonitrile

Preparation of 6-( 2-[(2, 4, -dichloro-6-nitro-l,l >-biphenyl-3-yl)amino]ethyl -amino)-nicotinonitrile... 

Design and synthesis of o-triflnoromethylbiphenyl substituted 2-amino-nicotinonitriles as inhibitors of famesyltransferase. Bioorg Med Chem Lett 15 153-158. 

To a well-stirred solution of 98% methylhydrazine (0.3 mL, 5.64 mmol) in anhyd MeCN (10 mL), cooled in an ice-water bath, was added 2-[(alkoxymethylene)aminopyridine-3-carbonitrile, prepared from 2-amino-nicotinonitrile (0.6 g, 5.7 mmol). The mixture was stirred overnight under N2. The solvent was removed on a Kugelrohr apparatus (25°C/0.7 Torr) to furnish the product which was obtained as a solid and recrystallized (McCN) as bright yellow needles yield 400 mg (46%) mp 156-158 C. 

Thus, refluxing 2-aminonicotinonitrile in triethyl orthoformate with26 or without14 acetic anhydride yields the (ethoxymethylene)amino compound, whose cyclization with ammonia yields pyrido[2,3-c/]pyrimidin-4-amine (18),14 while methylaminc affords 3-methylpyrido[2,3- /]pyrimidin-4(3//)-imine (41%).26 Dimethylformamide dimethyl acetal converts 2-aminonicotinonitrile into 2- [(dimethylamino)methylene]amino nicotinonitrile,14 which cyclizes with hy-droxylamine hydrochloride in methanol at room temperature to give pyrido[2,3-rf]pyrimidin-... 

Nitriles have also been used as cyclization partners. Thus, nicotinonitrile cyclizes with 2-amino-nicotinonitrile to give 2-(3-pyridyl)pyrido[2,3-r/]pyrimidin-4-amine (64).127 The electron-withdrawing effect of the pyridine group in nicotinonitrile, or of the trichloromethyl group in trichloroacetonitrile,128 appears to be essential for the reaction since benzonitrile does not react with 2-aminonicotinonitrile under the given conditions the dimer of 2-aminonicotinonitrile, 2-(2-amino-3-pyridyl)pyrido[2,3-r/]pyrimidin-4-amine,129 is obtained instead.127... 

The use of guanidine for cyclization gives amino substituted derivatives (e.g. 212) (52CB1012), and in this case o-aminonitriles may be used to furnish diamines (e.g. 8UOC1394). An unusual reaction involving nitriles occurred during the preparation of nicotinonitrile from the amide and ammonium sulfamate, when a 60% yield of the dimeric by-product (213) was formed via the nitrile (69BSB289). Similar products have been obtained from... 

For a related cyclization of 2-(eyanoamino)nicotinonitriles with hydrogen halides to give the corresponding 4-amino-2-halopyrido[2,3-t/]pyrimidones, see refs 549 and 550. 

The Vilsmeier-Haack reagent, prepared from dimethylformamide and phosphoryl chloride, converts 2-amino-5-(4-pyridyl)nicotinonitrile 1-oxide (45) into 7-chloro-6-(4-pyridyl)pyrido-[2,3-c/]pyrimidin-4(3f/)-one (46),72 this reaction also being an example of the conversion of an A-oxide into an st-chloro group. 

In a third synthesis of nicotine (373), nicotinonitrile (CLVI) was reacted with 7-ethoxypropyhnagnesium bromide (CLVII). The product of the reaction, 3-pyridyI-7-ethox3rpropylketone (CLVIII) formed an oxime (CLIX) which was reduced to a-(3-pyridyl)-o -amino-3-ethoxy-7i-butane (CLX) and this amino derivative, on heating to 150-155° with 48% hydrobromic acid was converted to dl-nomicotine (CLXI) which in turn has been methylated to dZ-nicotine ... 

Pyridines (218) can also be obtained, when arylethylidenemalononitriles 216 react with arylmethylidenemalononitriles 217 and 10. 201 was reacted with 10 and trichloroacetonitrile to yield 2-amino-4-phenyl-6-trichloromethyl-nicotinonitrile. Another three-component reaction yielded ethylthiopyridines 219. In this case the arylidenemalononitrile (179) condensed with 10 and EtSNa. ... 

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