2- Imino-2//-pyrido pyrimidine

A 9 1 mixture of 2,4-difluoro-4-pentafluoroethyl-3-trifluoromethyl-2//-, and 2,4-difluoro-2-pentafluoroethyl-3-trifluoromethyl-4//-, as well as 2-pentafluoroethyl-3-trifluoromethyl-4-oxo-4//-pyrido[l,2-n]pyrimidine were characterized by H, and NMR (00JFC105). 2-Trifluoromethyl-3-cyano-4-imino- and -4-oxo-4//-pyrido[l, 2-n]pyrimidines were characterized by and F NMR (00MI27). 

Reaction of 4-imino-4/f-pyrido[l, 2-n]pyrimidine-3-carbonitriles 124 with NaN3 in the presence of NH4CI gave 3-(2-pyridylamino)-2-(I//-tetrazol-5-yl)acrylonitriles 125 (93MIP3). 

The 3-formyl group of 8-substituted 3-formyl-2-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one was reacted with (cyanomethyl)- and (terr-butoxycarbo-nylmethylene)triphenylphosphorane in THF, and with 5-aminotetrazole in boiling MeOH for 9h to yield ( )-3-propenenitrile, terr-butyl ( )-3-propenoate and 3-[(2//-tetrazol-5-yl)imino]methyl derivatives, respectively (OlMIPl). 

Acidic hydrolysis of 4-imino-3-cyano-2-trifluoromethyl-4//-pyrido[l,2-n]pyrimidines in boiling EtOH with aqueous hydrochloric acid afforded 4-0X0 derivatives (00MI27). 

Heating the crystalline salt 2-aminopyridinium propiolate (346) at 100 °C in the solid state led to a 10 9 mixture of 2/f-pyrido[l,2-n]pyrimidin-2-one and ( )-3-(2-imino-l,2-dihydro-l-pyridyl)acrylic acid (347). Analysis of differental scanning calorimetry data shows unambiguously that the reaction takes place in the solid state. An endothermic peak at 81.1 °C corresponds to a solid state reaction, and a peak at 122-123 °C is attributed to melting. The product ratio of 2//-pyrido[l, 2-n]pyrimidin-2-one and 347 is 1 2.5 at 60°C, and 1 1.4 at 80°C (94MI12). 

Cyclocondensation of 2-iminopiperidine and 3-aryl-2-propynylnitriles in THE or 5% MeCN/THF afforded 4-aryl-2-imino-6,7,8,9-tetrahydro-2H- and 2-aryl-4-imino-6,7,8,9-terahydro-4//-pyrido[l,2-n]pyrimidines in 70-98% and 2-30% yields, respectively (00OL3389). When the reactions were carried out in the presence of 2 equiv of NaHMDS the product ratio was reversed. 

Reaction of 2-aminopyridine with ethyl 2-cyano-3-ethoxy-3-methyl-, -3-ethyl-, -3-phenylacrylates and ethyl 2-ethoxycarbonyl-3-ethoxy-3-methyl-, -3-phenylacrylates in boiling xylene yielded 2-substituted 4/f-pyrido[l,2-u]pyrimidine-3-carbonitriles and -3-carboxylates (99MI7). Similar reactions of 2-aminopyridine with 2-cyano-3-ethoxyacrylonitrile and its 3-methyl, 3-ethyl, -3-phenyl derivatives in boiling MeCN afforded 4-imino-4//-pyrido[l,2-u]-pyrimidine-3-carbonitrile and its 2-substituted derivatives. 

Reaction of 3-amino-2-cyano-4-[(phenylamino)(methylthio)methylene]-2-pentenedioate (408) with a large excess of 1,3-propanediamine afforded ethyl 6-imino-l, 2,3,4-tetrahydro-6//-pyrido[l, 2-n]pyrimidine-9-carboxylate (409) as depicted in Scheme 16 (95JHC477). 

Reaction of 4-cyano-3-imino-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyr-imidin-l-one 169 with 2-chloroethyl isocyanate at ambient temperature and under reflux gave N-acylated 170 and tetracyclic derivative 171, respectively (95MI1). Similar reaction of 3-amino-4-cyano-2,4a5,6,7,8-hexahydro-l// pyrido[l,2-c]pyrimidin-1-ones 172 afforded tricyclic compounds 173. 

Reaction of 2-cyanomethylpyridine with iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)-iV -(4-methylphenyl)carbodiimides, and with (1,1,2,2,2-pentachloro- and l,l-dichloro-2,2,2-trifluoroethyl)isocyanates or A-methoxycarbonyl-l,2,2,2-tetrachloro-, — l-chloro-2,2-trifluoroacetaldehyde imines afforded 3-aryl-4-cyano-l-(4-methylphenyl)imino-3-trifluoromethyl-2,3-dihydro-17/-pyrido[l,2-f]pyrimidines and 4-cyano-3-trichloro-, 4-cyano-3-trifluoro-17/-pyrido[l,2-4pyrimidin-l-ones, respectively <2004CHE47>. Refluxing 2-cyanomethylpyridine and iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)isocyanates in benzene furnished l-aryl-4-cyano-l-trifluoromethyl-l,2-dihydro-3//-pyrido[l,2-4pyrimidin-3-ones. However, when the solution of the isocyanate was added dropwise to the solution of 2-cyanomethylpyridine, and the reaction mixture was then treated with NEt at room temperature, the isomeric 3-aryl-4-cyano-3-trifluoromethyl-2,3-dihydro-l//-pyr-ido[l,2-dpyrimidin-l-ones were obtained. Reaction of l-(acetyl- and benzoylmethylene)-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinolines with PhCONCS yielded 1-acetyl-, 1 -benzoyl-9,10-dime thoxy-3-pheny 1-6,7-dihydro-2//-pyrimido[6,l- ]isoquinoline-2-thiones <2003SL2369>. 

Cyclocondensation of 2-iminopiperidine and 3-aryl-2-propynylnitriles afforded 4-aryl-2-imino-6,7,8,9-tetrahydro-22/-pyrido[l,2- ]pyrimidines <20000L3389, 2002W002/00629>. The minor isomers, 2-aryl-4-imino-6,7,8,9-tetrahy-dro-4/7-pyrido[l,2- ]pyrimidines could also be isolated in 2-30% yields from the reaction mixtures <20000L3389>. When the reactions were carried out in the presence of 2 equiv of NaHMDS, the product ratio was reversed. From the reaction mixture of 2-aminopyridine and perfluoro-2-methylpent-2-ene in MeCN, a 9 1 mixture of 2,4-difluoro-2-pentafluoroethyl-3-trifluoromethyl-477- and the isomeric 2,4-difluoro-4-pentafluoroethyl-3-trifluoromethyl-277-pyr-ido[l,2- ]pyrimidine (64%), and 2-pentafluoroethyl-3-trifluoromethyl-47/-pyrido[l,2- ]-pyrimidine-4-one (20%) was isolated <2000JFC(103)105>. 

Okamoto et a/.156 cyclized the dinitriles (86 R = CN, R2 = H) by heating in 15° hydrochloric acid to obtain pyrido[l,2-a]pyrimidine-3-carboxylic acids (89 R2 = H). 2-Aminopyridinium chloride and ethoxymethylene-malononitrile at 110CC yielded 3-cyano-4-imino-4H-pyrido[l,2-a]pyrimi-dine (87 R1 = R2 = H, X = NH) and compound 91. Under similar conditions, 2-amino-3-methylpyridine gave a noncyclized product of type 91. 

Okamoto et al. prepared the pyrido[l,2-c<]pyrimidines (142 R = H, Me) by heating 2-aminopyridines with ethyl 3-chloropropionimidate hydrochloride in ethanol or acetonitrile. In the case of 2-aminopyridine and 2-amino-4-methylpyridine, not only 142 (R = H, 8-Me) but also the 2-imino derivatives were isolated, which on treatment with acid were transformed to 2-oxopyrido[l,2-c<] pyrimidines (142). With 2-amino-6-methylpyridine or... 

The reaction with pyridone (167) was interpreted as proceeding by the formation of the pyridone (168), followed by the Smiles rearrangement leading to the spiro compound (169), which by ring opening provides the pyrimidine derivative (170). In a subsequent cyclization step the pyrido-[1,2-aJpyrimidine skeleton (171) is formed, and finally hydrolysis of the imino group leads to the 6-oxo derivative (172). In the homologous imidazo-[l,2-n]pyridine series, the 5-iminoimidazo[l,2-c<]pyridine intermediate of type (171) could be isolated. 

According to Kobayashi et ul.,268 4-oxo- and 4-imino-4f f-pyrido[l,2-a]-pyrimidine-3-nitriles can be reduced to the 6,7,8,9-tetrahydro compounds with sodium borohydride. Reduction of the hydroiodide of 41 (R = H) with sodium borohydride or lithium aluminimum hydride, however, was unsuccessful.2... 

Another way to prepare 2-amino derivatives is by the reaction of 2-methylthio-4-oxo-4// derivatives with amines.268,288 The 2-methylthio-4-imino derivative reacted differently (see Section III,C,8). 2-Ainino-4-oxo-4//-pyrido[l,2-a]pyrimidine could have also been prepared by reducing the 2-hydrazino derivative with hydrogen sulfide.289... 

Diethyl malonate in methanol in the presence of potassium carbonate transformed the 2-methylthio group of 93 (X = O) into a 2-methoxy group. If the solvent was dimethylformamide, the product was the malonic acid derivative (220).268 2-Methoxy-4-imino-4//-pyrido[l,2-a]pyrimidine was prepared from the corresponding 2-methythio derivative (93 X = NH) by treatment with methanolic sodium hydroxide.268... 

The thioxo group of 2,3-diphenyl-4-thioxo-4/f-pyrido [1,2-a] pyrimidine was converted with mercuric acetate to an oxo group.172,173 The imino group of 4-imino-4/f-pyrido[l,2-a]pyrimidines was hydrolyzed with acids to an oxo group.156,268... 

The 4-imino group of 3-cyano-4-imino-2-methylthio-4//-pyrido[ 1,2-a]-pyrimidine was transformed to the 4,4-diamino group with amines and to the 4-methylimino group with methyl iodide in dimethylformamide in the presence of potassium carbonate.268 On the action of dimethyl acetylenedi-carboxylate in dimethylformamide at 150°C, the 1,4-diazacycl [3,3,3] azine (234 R = CH3S) was formed.314... 

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