Pyridine-2-carbonitriles, 3-amino

The diazotized 3-amino-4-phenylpyrazolo[3,4- ]pyridine-5-carbonitrile 698 coupled with l-phenyl-3-methyl-5-pyrazolone 699 to yield 700, which cyclized (91G209) to the condensed pyrazolotriazine 701. 

In the presence of bis(acetylacetonato)nickel, a-dicarbonyl compounds readily add at the nitrile group of 4-R-substituted l,2,5-oxadiazole-3-carbonitriles 219 to form enaminofurazans 220. The adducts obtained from 4-amino-3-cyanofurazan underwent intramolecular cyclization upon heating with acetic acid in ethanol to give furazano[3,4- ]pyridine 221 derivatives in high yields (Scheme 51) <2001RCB1280>. 

A Vilsmeier reaction of pyridine-2-carbonitriles 126 was found to produce mixtures of l-formyl-2-dimethyl-amino[l,5-4]pyridines with a chlorine atom 127 or a hydrogen 128 at the C-7 position < 1998J(P 1 )3851 >. When extended to isoquinoline-1 -carbonitriles such as 129, this reaction gave in modest yield compounds 130 (Scheme 40). Later on, it was demonstrated that this reaction leads to imidazo[l,5- ]pyridinium chlorides when A,A-dimethylbenzamides were used instead of dimethylformamide (DMF) <1999H(50)887>. 

FIGURE 9 Moderately rapid gradient separation. Column XTerra MS C, IS, 4.6x 20mm 3.5p.m. Gradient 0 to 100% B over 4min,A 0.1% formic acid in water, B 0.1% formic acid in acetonitrile. Flow rate 3.0mL/min. Temperature 30°C. Detection UV at 254 nm. Instrument Alliance 2795 with 996 photodiode array detector. Compounds (I) acetanilide, (2) triamcinolone, (3) hydrocortisone, (4) 2-amino-7-chloro-5-oxo-5H-[l]benzopyrano[2,3-b]pyridine-3-carbonitrile, (5) 6a-methyl-17a-hydroxyprogesterone, (6) 3-aminofluoranthene, (7) 2-bromofluorene, (8) perylene, (9) naphtho(2,3-a)pyrene. 

Dichloro-5-methoxyphenyl)amino]thieno[3,2- ]pyridine-6-carbonitriles substituted with heteroaryl groups at position C-2, 160, have been found to inhibit Src kinase activity. The highest activity in Src and cell assays has been found with a 2,5-furan or 2,5-pyridine substituent at C-2 <2005BML4681, 2005JME3891>. 

Japanese workers recently designed a synthesis of 5-amino-2,3-dihydrothiepino[2,3- >]pyridine-4-carbonitrile 2 based on Thorpe-Ziegler cyclisation of 2-(3-cyanopropylthio)pyridine-3-carbonitrile 1. Treatment of 1 with potassium t-butoxide however, did not, give 2, but produced the thieno[2,3-/i][l,6]naphthyridine 3 in 82% yield. 

A mixture of 2 ml of morpholine, 3 ml of dimethylformamide and 10 ml of water was heated to 60°C and under stirring the equal molecular quantity of 6-isopropyl-4-oxo-4H-l-benzopyran-3-carbonitrile was added for 5 minutes. The mixture was heated at that temperature for one hour and the resultant precipitate was filtered, rained with water recrystallized from acetic acid and washed with chloroform. By the above procedure was obtained 2-amino-6-isopropyl-4-oxo-4H-l-benzopyran-3-carboxaldehyde melting at 206°-208°C. A mixture of 4 ml ethyl cyanoacetate, 50 ml of ethanol, 5 ml of piperidine and the equal molecular quantity of 2-amino-6-isopropyl-4-oxo-4H-l-benzopyran-3-carboxaldehyde was refluxed for 30 minutes and, after cooling, the crystalline precipitate was filtered and washed with chloroform. By above procedure was obtained ethyl-2-amino-7-isopropyl-l-azaxanthone-3-carboxylate, melting after recrystallization from ethanol at 243°-244°C. A mixture of 10 ml of acetic acid and 10 ml of 55% sulfuric acid the equal molecular quantity and 2-ethyl-amino-7-isopropyl-l-azaxanthone-3-carboxylate was stirred at 130°C for 4 hours and, after water was added, the precipitate was collected by filtration and recrystalllized from dimethylformamide to give the 2-amino-7-(l-methylethyl)-5-oxo-5H-[l]benzopyrano[2,3-b]pyridine-3-carboxylic acid, melting point 300°C. 

Keto-sulfones, which contain a 2-pyridyl ketone moiety, react with alkylidenemalononitriles to afford 2-amino-5-sulfonyl-4-aryl-6-(pyridin-2-yl)-47/-pyran-3-carbonitriles 86 (Equation 47) <1997JOC6575>. Likewise, (3-keto-sulfoxides featuring a 2-pyridyl ketone moiety react with alkylidenemalononitriles to form 2-amino-5-sulfinyl-4-aryl-6-(pyridin-2-yl)-4//-pyran-3-carbonitriles. Additionally, chiral (3-keto-sulfoxides that contain a 2-pyridyl ketone moiety can add to alkylidenemalononitriles with high stereoselectivity <1997JOC6575>. 

Methylamino-l,6-naphthyridine-3-carbonitrile (18, R = Me) underwent limited hydrolysis of its cyano group to afford 2-methylamino-l,6-naphthyridine-3-carboxamide (17) (KOH, H20, EtOH, reflux, 5 min 79%) the related substrate, 2-amino-l,6-naphthyridine-3-carbonitrile (18, R = H), underwent thiolysis of the cyano group to afford 2-amino-1,6-naphthyridine-3-car-bothioamide (19) (substrate, NEt3, pyridine, 20°C, H2S in, 2 h 97%) or hydrazinolysis of the cyano group to afford 2,N diamino -1,6-naphthyridine-3-carboxamidine (20) (H2NNH2.H2Q, reflux, 5 min 65%).247... 

Thiophenes are also readily available by treatment of 3-halocinnamonitriles with a-haloacetic acid derivatives in the presence of sodium sulfide and a base. In a stepwise route, the precursor 4 was converted to the intermediate 5, which was finally subjected to base induced cyclization giving the thiophene 6 <07SC1133>. Related annulation methodology has been used for construction of a series of 3-amino-5-arylthiophene-2-carbonitriles <07S1027>, and thieno[3,2-Z>]pyridine-5(477)-ones <07S2153>. 

Zhou and co-workers [62] have reported a series of 2-amino-6-(2-oxo-2//-chromen-3-yl)-4-pyridine-3-carbonitriles 11 by a one-pot, MCR of 3-acetyl-coumarin, an aromatic aldehyde, malononitrile, and ammonium acetate in acetic acid using a domestic microwave oven. Aromatic aldehydes bearing electron-withdrawing groups gave rather low yields of 11 (Scheme 11). 

Reaction of 6-methyl- or 6-styryl-2-phenyl-4-thioxopyrimidinc-5-carbonitrilc 3 with arylidene-malononitriles 4 in pyridine or with paraformaldehyde and malononitrile in dimethylform-amide/piperidine solution affords the 5-amino-2-phenyl-4-thioxo-3,4-dihydroquinazoline-6-carbonitriles 5 in moderate yields. 

A mixture of 4-amino-l-methylimidazok-5-carbonitrile (2.44g, 2mmol), ethyl isothiocyanate (5.22g, 6mmol), and pyridine (20mL) was heated to reflux for 1.5h. After cooling the solution, the pale-yellow solid was filtered and dissolved in a mixture of H,0 (50mL) and 4M HCl (5mL). After neutralizing with NH,OH, crystals were obtained yield 2.5g (60%) mp 252 -253"C. 

A solution of 4-amino-l,2-dimethylimidazole-5-carbonitrile (680mg, 5mmol) in pyridine (lOmL) was heated under reflux with CS, (lOmL) for 2h. After cooling the solution, the yellow solid was filtered, washed with MeOH and dissolved in 1 M NaOH. After neutralizing with 3M HOAc, the product was obtained yield 880mg (92%) mp > 360°C. 

Reaction of 5-amino-l-(2,3,5-tri-C)-benzyl-j -D-arabinofuranosyl)imidazole-4-carbonitrile with methyl isocyanate in pyridine followed by ammonia treatment yields 9-(/l-D-arabinofuranosyl)-1-mcthylisoguaninc 4. Dcbcnzylation to 5 was achieved wdth boron trichloride. ... 

A solution of 5-amino-l-(2,3.5-tri-(9-benzyl-j8-D-arabinofuranosyl)-4-carbonitrile (8.7 g, 17 mmol) and methyl isocyanate (120 mL) in anhyd pyridine (200 mL) was heated under reflux for 3 h. The mixture was cooled, evaporated to dryness, and coevaporated with MeOH. This syrup was dissolved in MeOH (375 mL), treated with coned NH OH (250 mL), and heated at 60 C for 3 h in a scaled flask. The solution was cooled, concentrated to a gum, dissolved in CHCI3 (20 mL), and loaded onto a silica column (4 x 100 cm). The column was eluted with CHClj/EtOH (25 1) and, after evaporation of the appropriate fractions, a waxy solid was obtained yield 6g (62%). 

Ethoxymethylenamino- 2-methyl-1,2,3-triazole-5-carbonitrile (90) (also its 1-methyl and 3-benzyl analogs), when refluxed with ethanolic sodium hydrogen sulfide for 10 h, produced 8-methyl-, 7-methyl-, and 9-ben-zyl-8-azapurine-6-thione in 83 - 97% yields. 4-Amino-1,2,3-triazole-5-car-bonitrile and its 2-methyl and 9-benzyl derivatives were refluxed (2 h) with potassium 0-ethyldithiocarbonate in dimethylformamide (or alternatively with carbon disulfide in pyridine) to produce 8-azapurine-X6-dithione (or its respective alkyl derivatives) in 88-95% yields. ... 

Amino-1-methyl-1,2,3-triazole-5-carbonitrile, when refluxed in pyridine with phenyl isothiocyanate, gave 6-anilino-7-methyl-8-azapurine-2-... 

A rather surprising product was furnished when 3-benzyl-A-methyl-formamidotriazole-5-carboxamide (17) was refluxed with ethanolic sodium ethoxide, namely, bis-(3-benzyl-4-methylaminotriazole-5-carbonyl)amine (44) (1 hr, 15%) [81JCS(P1)2344]. An unwanted incorporation of the solvent was found when 4-aminotriazole-5-carboxamide and thionyl chloride were stirred in pyridine, giving 4-amino-x-(y-pyridyl)-l,2,3-triazole-5-carbonitrile (4 C, 8 hr, 25%) [73JCS(P1)1629]. 

The introduction of a 2- [(ethoxycarbonyl)ethyl]amino group by nucleophilic substitution of the halogen in 3-chloropyridazine-4-carbonitriles (see Vol. E9a, p 631) gives ethyl 3-[(4-cyano-pyridazin-3-yl)amino]propanoates, which can be used for Dieckmann-Ziegler type cycliza-tions to construct the pyridine moiety of ethyl 8-alkyl-5-amino-7,8-dihydropyridazine-6-car-boxylates 9.20... 

The acetimidamide side chain originating from the reaction of the amino group in 3-aminopy-ridazine-4-carbonitrile with A.A-dimethylacetamide dimethyl acetal (vide infra) has been used for pyridine ring closure. Thus, treatment of 3- [(l-dimethylamino)ethylidene]amino pyrid-azine-4-carbonitrilc with lithium diisopropylamide at — 70°C gives 7V, (V7-dimethylpyrido-[2,3-c]pyridazine-5,7-diamine (10).21... 

If the coupling reaction of ethyl (4,6-diamino-3,5-dicyano-2-pyridyl)acetate with benzenediazonium chloride is performed in pyridine at 0°C, an oil results which, by refluxing in dimethylformamide, gives the cyclization product.64 In a one-pot reaction, 2-amino-3-benzoyl-5-cyano-4-phenylpyridine-6-acetonitrile, or the corresponding ethyl acetate, is coupled with benzenediazonium chloride in aqueous ethanolic sodium hydroxide, the mixture then left at room temperature to give 2-amino-3-benzoyl-5-imino-4,6-diphenyl-5,6-dihydropyrido[2,3-fi(]-pyridazine-8-carbonitrile (22a) or the ethyl 8-carboxylate 22b.65... 

Under the catalytic action of trifluoroacetic acid, 2-aininonicotinonitrile and trimethyl orthoformate react to yield 2-[(methoxymethylene)amino]pyridine-3-carbonitrile, the starting material for the cyclization with methylhydrazine. Whereas at 0 °C the reaction provides a 1 1 mixture of the cis/truns-isomers of A,-amino-,V-(3-cyano-2-pyridyl)-A-methylforrnimidamide, the same reaction at room temperature yields 4-(/ -methylhydrazino)pyrido[2,3-d]pyrimidine (17).25... 

Ethoxymethylene)amino]pyridine-3-carbonitrile, prepared from 2-aminonicotinonitrile with triethyl orthoformate and trifluoroacetic acid14 or acetic anhydride,26 upon treatment with ammonia yields pyrido[2,3-c/ pyrimidin-4-amine (18).14... 

Besides formyl, other acyl groups such as acetyl or benzoyl in the 5-position of the pyrimidine nucleus have been used for cyclizations. Thus, 5-acyl-6-aminopyrimidin-4(3//)-ones condense with malononitrile in refluxing pyridine to give the corresponding 7-amino-4-oxo-3,4-dihydropyrido[2,3-(7]pyrimidine-6-carbonitriles 21.171... 

By cyclization with hydroxylamine hydrochloride at room temperature, 4- [(7V,/V-dimethy]-amino)methylene]amino pyridine-3-carbonitrile yields pyrido[4,3-rf]pyrimidin-4-amine 3-oxide.452 Due to traces of hydroxylamine hydrochloride, the attempted rccrystallization of the crude product from dimethylformamide furnishes 4-(hydroxyamino)pyrido[4,3-Dimroth rearrangement is avoided by removal of the impurities by suspending the crude product in water (see Section 7.2.2.4.1.1.1.). 

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