5.6- Dihydropyrido

A major type of reaction in this class is the cyclization of 4-amino- or 4-halo-pyrimidines carrying 5-cyanoethyl or 5-ethoxycarbonylethyl groups, which cyclize to 7-amino or 7-oxo derivatives of 5,6-dihydropyrido[2,3- f]pyrimidine, e.g. (131)->(63). The intermediates may sometimes be prepared by reaction of 4(6)-aminopyrimidines with acrylonitrile, or even via a pyrimidine ring synthesis from an amidine and a cyanoacetic ester or malononitrile derivative, e.g. (132) -> (133) (7lJOC2 85, 72BCJ1127). 

Early reports of analgesic and antiarthritic activity in octahydropjTido[4,3-d]pyrimidines do not appear to have been substantiated, but a number of recent patents refer to the antipyretic, diuretic, bacteriostatic, sedative, and coronary-dilating activities of a series of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines. Pharmacological properties claimed for, 5,6-dihydropyrido[2,3-[Pg.198]

The stereostructure of ethyl OT-4a,7-//-7-phenyl-8-cyano-2-oxo-2,3,4,4a,7,8-hexahydropyrido[l,2-A [l,2]oxazine-8-carboxylate was confirmed by X-ray crystallography. It confirmed a trans-nng junction <20000L4007>. The structure of 2,4-diphenyl-7-o-hydroxyphenyl-5,6-dihydropyrido[2,Ttf]phthalazinium perchlorate 21 has also been established by X-ray crystallographic analysis <1995IZV296>. 

Brief photocyclization of pyridinium derivative 55 afforded 2,4-diphenyl-7-substituted 5,6-dihydropyrido[2,l-tf]-phthalazinium salts 56 (Equation 10) <1995IZV296>. 

The Structure of a pyrido[l,2-6]cinnoline (17, R = Br) (74JHC125), a pyrido[2,l-a]phthalazine (26) (94T9189), and 2,4-diphenyl-7-o-hydroxyphe-nyl-5,6-dihydropyrido[2,l-fl]phthalazinium perchlorate (27) (95IZV296) have been established by X-ray crystallographic analysis. 

Reaction of 6-amino-l,3-dimethyluracil with the Mannich base 524 under nitrogen in boiling H2O gave 5,6-dihydropyrido[2,3- pyrimidine-(17/,37/)-2,4-diones 531 rather than their oxidized analogues 530. The latter could be obtained by boiling the reactants in AcOH (Scheme 22) <2004T11511>. 

Dihydropyrido[2,3-6][l,5]benzothiazepin-5(6//)-ones (104) were obtained by cyclocondensation of 5 and 2-chloronicotinic acid (103) the reaction of compounds 104 with phosphorus oxychloride and phosphorus pentachloride afforded the corresponding iminochlorides which were refluxed in toluene with piperazines and triethylamine to give compounds 105. These products showed antihistaminic, orexigenic, and antianaphy-... 

Deprotonation of an 8,10-diphenyl-6-oxo-5,6-dihydropyrido[l,2-a] quinoxalinium salt gave the zwitterionic pyrido[l,2-a]quinoxalinium-6-olate [84JHC1609, 84KFZ(6)700], which underwent N-methylation on the action of CF3S03Me (84JHC1609). 

Methyl-5-oxo-5,6-dihydropyrido 2,3-d]pyridazine 1-Oxide (13) Typical Procedure 6... 

Using monoalkylhydrazines, mixtures of the 6-alkyl-5,6-dihydropyrido[2,3-af]pyridazin-5-ols and 7-alkyl-7,8-dihydropyrido[2,3-r(]pyridazin-8-ols are obtained.47... 

The coupling of ethyl (4,6-diamino-3,5-dicyano-2-pyridyl)acetate with benzenediazonium chloride in aqueous ethanolic sodium hydroxide solution produces the corresponding phenylhydra-zone, which is cyclized in refluxing acetic acid to give ethyl 2,4-diamino-3-cyano-5-imino-6-phenyl-5,6-dihydropyrido[2,3-a(]pyridazine-8-carboxylate,34 or in refluxing ethanolic sodium hydroxide to give ethyl 2,4-diamino-5-oxo-6-phenyl-5.6-dihydropyrido[2,3-t/]pyridazine-8-car-boxylate35 (see p 14). 

Aminoprop-l-ene-l,l,3-tricarbonitrile ( malononitrile dimer ) condenses with mesoxalo-dinitrile arylhydrazones to give 2,4-diamioo-6-aryl-5-imino-5,6-dihydropyrido[2,3-(/]pyridazine-3,8-dicarbonitriles l.29... 

In 7-[(methoxycarbonyl)methyleoejfuro[3,4-/)]pyridin-5(7//)-ooe, the enol-lactone ring can be opened by 4-nitrophenylhydrazine in acetic acid or ethanol, the resulting hydrazine cyclizes to give methyl 6-(4-nitrophenyl)-5-oxo-5,6-dihydropyrido[2,3-t/]pyridazine-8-acetate (2).54... 

The oxidative removal of a benzyl group by potassium hexacyanoferrate(III) provides a useful synthetic route, especially in the presence of functional groups labile to permanganate oxidation. It can be applied to 7-aryl-5-benzyl-l,4-dimorpholino-5,6-dihydropyrido[3,4- 7]pyrid-azines 1 giving products 2.119... 

Oxidation of 7-Aryl-5-benzyl-l, 4-dimorpholino-5,6-dihydropyrido 3,4-[Pg.60]

On addition of methyllithium in tetrahydrofuran/diethyl ether, pyrido[3,4-r/]pyridazine gives a 1 1 mixture of the two isomeric 1,2- and 4,3-addition compounds, i.e. 1-methyl-1,2-dihydropy-rido[3,4-r/]pyridazine (10) and 4-methyl-3,4-dihydropyrido[3,4-<7]pyridazine (11), which are readily oxidized by air to yield the fully aromatic systems (see Section 7.2.1.5.1.3).6 129 If the pyridazine ring is deactivated by amino substituents as in l,4-dimorpholino-7-phenylpyri-do[3,4-r/ pyridazine or its 5-methyl derivative, addition of organometallics such as benzyllithi-um, benzylmagnesium chloride or rcrt-butylmagnesium bromide occurs at the pyridine ring and yields 5-alkyl-5-methyl-l,4-dimorpholino-7-phenyl-5,6-dihydropyrido[3,4-d]pyridazines 12.119... 

A related cyclization may be involved in the one-pot reaction of diethyl 2-cyanoglutarate or its 4-methyl derivative (R = H) with guanidine to afford 2-amino-5,6-dihydropyrido[2,3-rf]-pyrimidine-4,7(3//,8//)-diones 5.406... 

Catalyzed by benzyltrimethylammonium hydroxide, acrylonitrile and 6-aminopyrimidine-2,4(17/,3//)-diones in pyridine/water afford the corresponding 7-amino-5,6-dihydropyrido-[2,3-aT]pyrimidine-2,4(l H,3H )-diones.368... 

Methyl-5,6-dihydropyrido[2,3- /]pyrimidin-7(8//)-one has been oxidized by selenium dioxide in acetic acid.210-211... 

Amino-4-bromo-5-methyl-5,6-dihydropyrido[2,3-sulfuric acid in acetic acid/ethanol.3 5... 

Instead of the ester function as in the examples above, a (dimethylamino)methylene group may be used in a similar way to incorporate a carbon atom into the pyrimidine part of 5,6-dihy-dropyrido[.3.4-<7 pyrimidin-8(7//)-oncs. The reaction of 4-[(iV,A -dimethylamino)methylenc]-piperidine-2,3-dione (14) with guanidine, thiourea, or acetamidine yields the corresponding 5,6-dihydropyrido[3,4- /]pyrimidin-8(7//)-one 15 in low yield.474... 

The lactone obtained from 5-(/j-hydroxyethyl)orotic acid or the corresponding thiolactone has been converted into 5,6-dihydropyrido[3,4-d]pyrimidine-2,4,8(17/,3ff,7//)-trione by am-monolysis.89... 

The reaction of 2-aminoprop-l-ene-l,l,3-tricarbonitrile ( dimeric malononitrile ) with dimethylformamide dimethyl acetal occurs at both the amino and the methylene group and yields a biscondensation product 1. By heating this compound with aliphatic or aromatic amines, various 6-substituted 4-amino-5-imino-5,6-dihydropyrido[4,3-tf]pyrimidine-8-carboni-triles 2 are obtainable, the presumed mechanism including a Dimroth rearrangement (cf. p 90) in the pyrimidine part of the molecule.494... 

In the course of the reaction of 4-methyl-2-phenylpyrimidine-5-carboxylic acid with di-cthylformamidc/phosphory] chloride to give 6-cthyl-5-oxo-2-phenyl-5,6-dihydropyrido[4,3-J]pyrimidine-8-carbaldehyde, the aldehyde function in the 8-position is introduced by a Vilsmeier formylation520 (see Section 7.2.2.4.1.1.3,). 

The imino function in various 6-substituted 4-amino-5-imino-5,6-dihydropyrido[4,3-t/J-pyrimidine-8-carbonitriles has been converted into the corresponding 5-oxo group by acid hydrolysis.494... 

Both pyrido[2,3-/)]pyrazine and its 2,3-dimethyl derivative undergo Reissert compound formation by treatment with trimethylsilyl cyanide, benzoyl chloride, and a catalytic amount of aluminum trichloride. The Reissert compound from pyrido[2,3-f>]pyrazine, 5-benzoyl-5,6-dihydropyrido-[2,3-/)]pyrazine-6-carbonitrile, is bismethylated in the 6- and 8-positions by iodomethane in dimethylformamide in 22% yield.88... 

Mcthylpyrido[2,3-7>]pyrazinium iodide is reduced by potassium borohydride to give the air-sensitive 5-methyl-5,6-dihydropyrido[2,3-6]pyrazine in 60% yield14 (cf. Section 7.2.3.1.1.3.). 

By refluxing [6-amino-3-(ethoxycarbonyl)pyrazin-2-yl]- or (6-amino-3-cyanopyrazin-2-yl)-malononitriles in acetic acid/hydrochloric acid, the malononitrile moiety is converted into the corresponding malonamide. This cyclizes with one of its amido groups with the ortho substituent to give eventually 2-amino-7-hydroxy-5-oxo-5,6-dihydropyrido[3,4-/)]pyrazine-8-Carbox-... 

Reissert compounds and analogs alkylated in the 5-position, such as ethyl 5-cyano-5-methyl-2.3-diphenyl-5,6-dihydropyrido[3.4-/)]pyrazine-6-carboxylate (5, R = Me), are hydrolyzed by refluxing in cthanolic aqueous potassium hydroxide, followed by decarboxylation and dehydrocyanation to yield the 5-alkylated 2,3-diphenylpyrido[3,4-h]pyrazines 6."3... 

Starting from 6-benzoyl-2,3-diphenyl-5,6-dihydropyrido[3,4-6]pyrazine-5-carbonitrile (7), alkylation in the 5-position by iodomethane or benzyl bromide in dimethylformamide/sodium hydride directly furnishes 5-alkyl-2,3-diphenylpyrido[3,4-6]pyrazines 8.1,3... 

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